Mitotic kinesin inhibitors and methods of use thereof

ABSTRACT

This invention relates to inhibitors of mitotic kinesins, particularly KSP, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders.

RELATED APPLICATIONS

The present application is a Divisional application under 37 C.F.R.1.53(b) of U.S. Ser. No. 12/043,456, filed Mar. 6, 2008 now U.S. Pat.No. 7,956,073, which is a Divisional application of application Ser. No.11/252,232, now U.S. Pat. No. 7,449,486, filed Oct. 17, 2005, and claimspriority of U.S. Provisional Patent Application No. 60/620,048, filedOct. 19, 2004 and which applications are incorporated by referenceherein in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel inhibitors of mitotic kinesins, inparticular the mitotic kinesin KSP, pharmaceutical compositionscontaining the inhibitors, and methods for preparing these inhibitors.The compounds of this invention are useful for the treatment of diseasesthat can be treated by inhibiting mitosis, including cellularproliferative diseases, for example cancer, hyperplasias, restenosis,cardiac hypertrophy, immune disorders, fungal infections, andinflammation.

2. Description of the State of the Art

Among the therapeutic agents used to treat cancer are the taxanes andvinca alkaloids, which act on microtubules. Microtubules are the primarystructural elements of the mitotic spindle, which is responsible fordistribution of replicate copies of the genome to each of the twodaughter cells that result from cell division. It is presumed thatdisruption of mitotic spindle by these drugs results in inhibition ofcancer cell division and induction of cancer cell death. However,microtubules form other types of cellular structures, including tracksfor intracellular transport in nerve processes. Because drugs such astaxanes and vinca alkaloids do not specifically target mitotic spindles,they have side effects that limit their usefulness.

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest, in part because of the improved therapeuticbenefits which would be realized if the side effects associated withadministration of these agents could be reduced. Traditionally, dramaticimprovements in the treatment of cancer have been associated withidentification of therapeutic agents acting through novel mechanisms.Examples include not only the taxanes, but also the camptothecin classof topoisomerase I inhibitors. From both of these perspectives, mitotickinesins are attractive targets for new anti-cancer agents.

Mitotic kinesins are enzymes essential for assembly and function of themitotic spindle, but are not generally part of other microtubulestructures such as nerve processes. Mitotic kinesins play essentialroles during all phases of mitosis. These enzymes are “molecular motors”that transform energy released by hydrolysis of ATP into mechanicalforce, which drives the directional movement of cellular cargoes alongmicrotubules. The catalytic domain sufficient for this task is a compactstructure of approximately 340 amino acids. During mitosis, kinesinsorganize microtubules into the bipolar structure that is the mitoticspindle. Kinesins mediate movement of chromosomes along spindlemicrotubules, as well as structural changes in the mitotic spindleassociated with specific phases of mitosis. Experimental perturbation ofmitotic kinesin function causes malformation or dysfunction of themitotic spindle, frequently resulting in cell cycle arrest and celldeath.

Among the identified mitotic kinesins is kinesin spindle protein (KSP).KSP belongs to an evolutionarily conserved kinesin subfamily of plusend-directed microtubule motors that assemble into bipolar homotetramersconsisting of antiparallel homodimers. During mitosis, KSP associateswith microtubules of the mitotic spindle. Microinjection of antibodiesdirected against KSP into human cells prevents spindle pole separationduring prometaphase, giving rise to monopolar spindles and causingmitotic arrest and induction of programmed cell death. KSP and relatedkinesins in other non-human organisms bundle antiparallel microtubulesand slide them relative to one another, thus forcing the spindle polesapart. KSP may also mediate in anaphse B spindle elongation and focusingof microtubules at the spindle pole.

Human KSP (also termed HsEg5) has been described (Blangy, et al., Cell,83:1159-69 (1995); Whitehead, et al., Arthritis Rheum., 39:1635-42(1996); Galtio, et al., J. Cell Biol., 135:339-414 (1996); Blangy, etal., J. Bio. Chem., 272:19418-24 (1997); Blangy, et al., Cell MotilCytoskeleton, 40:174-82 (1998); Whitehead and Rattner, J. Cell Sci.,111:2551-61 (1998); Kaiser, et al., JBC, 274:18925-31 (1999); GenBankaccession numbers: X85137, NM004523 and U37426), and a fragment of theKP gene (TRIP5) has been described (Lee, et al., Mol. Endocrinol.,9:243-54 (1995); GenBank accession number L40372). Xenopus KSP homologs(Eg5), as well as Drosophila K-LP61 F/KRP 130 have been reported. Smallmolecule inhibitors of KSP have recently been described: Mayer, et al.,Science, 286:971-4 (1999); Maliga, et al., Chemistry and Biology,9:989-96 (2002) Sakowicz, et al., Cancer Research 64:3276-80 (2004);Yan, et al., J. Mol. Biol. 335:547-554 (2004); Coleman, et al., ExpertOpin. Ther. Patents 14(12):1659-67 (2004); Cox, et al., Bioorg. Med.Chem. Lett. 15:2041-5 (2005); Gartner, et al., ChemBioChem 6:1173-7(2005); Bergnes, et al., Current Topics in Medicinal Chemistry 5:127-45(2005); and in PCT Publication Nos. WO 00/130,768, WO 01/30768, WO01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO03/049,678, WO 03/051854, WO 03/39460 WO 03/079,973, WO 03/088,903, WO03/094,839, WO 03/097,053, WO 03/099,211, WO 03/099,286, WO 03/103,575,WO 03/105,855, WO 03/106,426, WO 04/032,840, WO 04/034,879, WO04/037,171, WO 04/039,774, WO 04/055,008, WO 04/058,148, WO 04/058,700,WO 04/064,741, WO 04/092147, WO 04/111023, WO 04/111024, WO 05/035512,WO 05/017190, WO 05/018547, and WO 05/019206.

Mitotic kinesins are attractive targets for the discovery anddevelopment of novel mitotic chemotherapeutics. Accordingly, it is anobject of the present invention to provide compounds, methods andcompositions useful in the inhibition of the mitotic kinesin KSP.

SUMMARY OF THE INVENTION

This invention provides compounds that are useful in treating diseasesthat can be treated by inhibiting mitosis. In particular, one aspect ofthis invention provides compounds and pharmaceutical compositionsthereof that inhibit mitotic kinesins, and in particular the mitotickinesin KSP. Such compounds have utility as therapeutic agents fordiseases that can be treated by the inhibition of the assembly and/orfunction of microtubule structures, including the mitotic spindle. Ingeneral, the invention relates to compounds of the general Formula I:

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts and prodrugs thereof,wherein:

X is O, S, S(O) or S(O)₂;

R is Z—NR²R³, Z—OH, or Z—OP(═O)(OR^(a))(OR^(a));

R¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturatedheterocycloalkyl, —OR³, —NR⁴OR⁵, CR^(b)(═NOR^(c)), C(═O)R^(a), or—NR⁴R⁵, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on said aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), —OP(═O)(OR^(a))₂, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

Ar¹ and Ar² are independently aryl, heteroaryl, saturated or partiallyunsaturated cycloalkyl, or saturated or partially unsaturatedheterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, cyano, nitro, alkyl, alkenyl,alkynyl, saturated or partially unsaturated cycloalkyl, saturated orpartially unsaturated heterocycloalkyl, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OR^(a),—O(C═O)OR^(d), —OP(═O)(OR^(a))(OR^(a)), NR^(a)R^(b), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), SR⁶, SOR⁶, SO₂R⁶, —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b) and —NR^(c)C(═O)NR^(a)R^(b);

R² is hydrogen, —C(═O)R⁴, —SO₂R⁶, —C(═O)NR⁴R⁵, —SO₂NR⁴R⁵, —C(═O)OR⁶,alkyl, alkenyl, alkynyl, aryl, heteroaryl, saturated or partiallyunsaturated heterocycloalkyl, saturated or partially unsaturatedcycloalkyl, a natural or unnatural amino acid, or a polypeptide of twoor more amino acids independently selected from natural and unnaturalamino acids, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocycloalkyl, and cycloalkyl are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on said aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;

R³ is hydrogen, —C(═O)R⁴, —C(═O)NR⁴R⁵, alkyl, alkenyl, alkynyl, aryl,heteroaryl, saturated or partially unsaturated heterocycloalkyl, orsaturated or partially unsaturated cycloalkyl, wherein said alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —OP(═O)(OR^(a))₂, —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b),—C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d),—NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl,

or R² and R³ together with the nitrogen atom to which they are attachedform a saturated or partially unsaturated heterocyclic ring which mayinclude 1 to 3 additional heteroatoms, in addition to the nitrogen atomto which said R² and R³ are attached, selected from N, O and S, whereinsaid heterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;

R⁴ and R⁵ are independently H, OR^(a), trifluoromethyl, difluoromethyl,fluoromethyl, alkyl, alkenyl, alkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturatedheterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl,

or R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring which may include 1to 3 additional heteroatoms, in addition to the heteroatoms to whichsaid R⁴ and R⁵ are attached, selected from N, O and S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;

R⁶ is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturatedor partially unsaturated heterocycloalkyl, aryl or heteroaryl, whereinsaid alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl;

R^(a) is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturatedor partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, saturated or partially unsaturatedheterocycloalkyl or heterocyclylalkyl, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(h), —NR^(f)SO₂R^(h), —SO₂NR^(e)R^(f), —C(═O)R^(e),—C(═O)OR^(e), —OC(═O)R^(e), —NR^(f)C(═O)OR^(h), —NR^(f)C(═O)R^(e),—C(═O)NR^(e)R^(f), —NR^(e)R^(f), —NR^(g)C(═O)NR^(e)R^(f),—NR^(c)C(NCN)NR^(e)R^(f), —OR^(e), alkyl, alkenyl, alkynyl, saturated orpartially unsaturated cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl andheterocyclylalkyl;

R^(b), R^(c), R^(f) and R^(g) are independently are hydrogen or alkyl,

or R^(a) and R^(b) together with the atom to which they are attachedform a 4 to 10 membered saturated or partially unsaturated heterocyclicring which may include 1 to 3 additional heteroatoms, in addition to thenitrogen atom to which said R^(a) and R^(h) are attached, selected fromN, O and S;

R^(d) and R^(h) are independently trifluoromethyl, alkyl, saturated orpartially unsaturated cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl orheterocyclylalkyl;

R^(e) is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturatedor partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, saturated or partially unsaturatedheterocycloalkyl or heterocyclylalkyl; and

Z is alkylene having from 1 to 6 carbons, or alkenylene or alkynyleneeach having from 2 to 6 carbons, wherein said alkylene, alkenylene andalkynylene are optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, C₂-C₁₀ alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl.

Another aspect of this invention relates to kinesin inhibitors of thegeneral Formula II:

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts and prodrugs thereof,wherein R, R¹, Ar¹ and Ar² are as defined above.

Yet another aspect of this invention provides a compound of Formula III

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts thereof, wherein R, R¹,Ar¹ and Ar² are as defined above.

Another aspect of this invention provides a compound of Formula IV

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts and prodrugs thereof,wherein R, R^(a), Ar¹ and Ar² are as defined above, and

R^(x) and R^(y) are independently H, alkyl, saturated or partiallyunsaturated cycloalkyl or aryl, wherein said alkyl, cycloalkyl and arylare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on saidaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d),—NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl,

or R^(x) and R^(y) together with the atom to which they are attachedform a saturated or partially unsaturated carbocyclic ring orheterocyclic ring having one or more heteroatoms independently selectedfrom N, O and S, wherein said carbocyclic and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl;

wherein R^(a), R^(b), R^(c) and R^(d) are as defined above,

or R^(a) and R^(x) together with the atoms to which they are attachedform a saturated or partially unsaturated heterocyclic ring which mayinclude 1 to 3 additional heteroatoms, in addition to the oxygen atom towhich said R^(a) is attached, selected from N, O and S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(h), —NR^(f)SO₂R^(h),—SO₂NR^(e)R^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—NR^(f)C(═O)OR^(h), —NR^(f)C(═O)R^(e), —C(═O)NR^(e)R^(f), —NR^(e)R^(f),—NR^(g)C(═O)NR^(e)R^(f), —NR^(c)C(NCN)NR^(e)R^(f), —OR^(e), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl, wherein R^(e),R^(f), R^(g) and R^(h) are as defined above.

Methods of making compounds of Formulas I-IV are also described.

In a further aspect the present invention provides compounds thatmodulate mitotic spindle formation comprising compounds of FormulasI-IV, and metabolites, solvates, resolved enantiomers, diastereomers,racemic mixtures and pharmaceutically acceptable salts and in vivocleavable prodrugs thereof.

In a further aspect the present invention provides a method of treatingdiseases that can be treated by blocking or inhibiting mitosis in ahuman or animal, which comprises administering to a warm-blooded animalan effective amount of a compound of Formula I-IV, or a metabolite,solvate, resolved enantiomer, diastereomer, racemic mixture orpharmaceutically acceptable salt or prodrug thereof, or a pharmaceuticalcomposition comprising said compound. Examples of diseases that can betreated by administration of compounds of this invention include, butare not limited to, abnormal or unwanted cell growth conditions, suchas, but not limited to, cellular proliferative diseases, for example,cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders,infectious disease, fungal or other eukaryote infections, inflammatorydiseases, arthritis, graft rejection, inflammatory bowel disease,proliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like.

In a further aspect the present invention provides a method ofinhibiting abnormal or unwanted cell growth, comprises administering tosaid abnormal or unwanted cells an effective amount of a compound ofFormula I-IV, or a metabolite, solvate, resolved enantiomer,diastereomer, racemic mixture or pharmaceutically acceptable salt orprodrug thereof.

In a further aspect the present invention provides a method of providinga mitotic kinesin inhibitory effect comprising administering to awarm-blooded animal an effective amount of a compound of Formula I-IV,or a metabolite, solvate, resolved enantiomer, diastereomer, racemicmixture or pharmaceutically acceptable salt or prodrug thereof.

The invention also relates to pharmaceutical compositions comprising acompound of Formula I-IV or a metabolite, solvate, resolved enantiomer,diastereomer, racemic mixture or pharmaceutically acceptable salt orprodrug thereof.

The inventive compounds may be used advantageously in combination withother known therapeutic agents. Accordingly, this invention also relatesto pharmaceutical compositions comprising a therapeutically effectiveamount of a compound of Formula I-IV or a metabolite, solvate, resolvedenantiomer, diastereomer, racemic mixture or pharmaceutically acceptablesalt or prodrug thereof, in combination with a second therapeutic agent.

In a further aspect the present invention provides a method of using acompounds of this invention as a medicament to treat a disease orcondition in a mammal that can be treated by blocking or inhibitingmitosis. For example, in certain aspects this invention provides amethod for treatment of a hyperproliferative disorder in a mammalcomprising administrating to said mammal one or more compounds ofFormula I-IV, or a metabolite, solvate, resolved enantiomer,diastereomer, racemic mixture or pharmaceutically acceptable salt orprodrug thereof, in an amount effective to treat said disease ordisorder. In other aspects, this invention provides a method of treatinga fungal or other eukaryote infection in a mammal, comprisingadministrating to said mammal one or more compounds of Formula I-IV, ora metabolite, solvate, resolved enantiomer, diastereomer, racemicmixture or pharmaceutically acceptable salt or prodrug thereof, in anamount effective to treat said infection.

An additional aspect of the invention is the use of a compound ofFormulas I-IV in the preparation of a medicament for the treatment orprevention of a disease or condition in a mammal that can be treated byblocking or inhibiting mitosis.

This invention further provides kits comprising one or more compounds ofFormula I-IV. The kit may further comprise a second compound orformulation comprising a second pharmaceutical agent for treating adisease that can be treated by inhibiting mitosis. In certainembodiments, the second agent is a compound having, for example,anti-hyperproliferative or antifungal activity.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The inventive compounds are useful for inhibiting mitotic kinesins andmicrotubule-mediated events such as mitotic spindle production. Suchcompounds have utility as therapeutic agents for diseases that can betreated by the inhibition of mitosis. In general, one aspect of theinvention relates to compounds of the general Formula I:

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts and prodrugs thereof,wherein:

X is O, S, S(O) or S(O)₂;

R is Z—NR²R³, Z—OH, or Z—OP(═O)(OR^(a))(OR^(a));

R¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturatedheterocycloalkyl, —OR³, —NR⁴OR⁵, CR^(b)(═NOR^(c)), C(═O)R^(a), or—NR⁴R⁵, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on said aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), —OP(═O)(OR^(a))₂, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

Ar¹ and Ar² are independently aryl, heteroaryl, saturated or partiallyunsaturated cycloalkyl, or saturated or partially unsaturatedheterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl, andheterocycloalkyl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, cyano, nitro, alkyl, alkenyl,alkynyl, saturated or partially unsaturated cycloalkyl, saturated orpartially unsaturated heterocycloalkyl, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OR^(a),—O(C═O)OR^(d), —OP(═O)(OR^(a))(OR^(a)), NR^(a)R^(b), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), SR⁶, SOR⁶, SO₂R⁶, —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b) and —NR^(c)C(═O)NR^(a)R^(b);

R² is hydrogen, —C(═O)R⁴, —SO₂R⁶, —C(═O)NR⁴R⁵, —SO₂NR⁴R⁵, —C(═O)OR⁶,alkyl, alkenyl, alkynyl, aryl, heteroaryl, saturated or partiallyunsaturated heterocycloalkyl, saturated or partially unsaturatedcycloalkyl, a natural or unnatural amino acid, or a polypeptide of twoor more amino acids independently selected from natural and unnaturalamino acids, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocycloalkyl, and cycloalkyl are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on said aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;

R³ is hydrogen, —C(═O)R⁴, —C(═O)NR⁴R⁵, alkyl, alkenyl, alkynyl, aryl,heteroaryl, saturated or partially unsaturated heterocycloalkyl, orsaturated or partially unsaturated cycloalkyl, wherein said alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —OP(═O)(OR^(a))₂, —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b),—C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d),—NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl,

or R² and R³ together with the nitrogen atom to which they are attachedform a saturated or partially unsaturated heterocyclic ring which mayinclude 1 to 3 additional heteroatoms, in addition to the nitrogen atomto which said R² and R³ are attached, selected from N, O and S, whereinsaid heterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;

R⁴ and R⁵ are independently H, OR^(a), trifluoromethyl, difluoromethyl,fluoromethyl, alkyl, alkenyl, alkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturatedheterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl,

or R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring which may include 1to 3 additional heteroatoms, in addition to the heteroatoms to whichsaid R⁴ and R⁵ are attached, selected from N, O and S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;

R⁶ is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturatedor partially unsaturated heterocycloalkyl, aryl or heteroaryl, whereinsaid alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl;

R^(a) is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturatedor partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, saturated or partially unsaturatedheterocycloalkyl or heterocyclylalkyl, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(h), —NR^(f)SO₂R^(h), —SO₂NR^(e)R^(f), —C(═O)R^(e),—C(═O)OR^(e), —OC(═O)R^(e), —NR^(f)C(═O)OR^(h), —NR^(f)C(═O)R^(e),—C(═O)NR^(e)R^(f), —NR^(e)R^(f), —NR^(g)C(═O)NR^(e)R^(f),—NR^(c)C(NCN)NR^(e)R^(f), —OR^(e), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl;

R^(b), R^(c), R^(f) and R^(g) are independently are hydrogen or alkyl,

or R^(a) and R^(b) together with the atom to which they are attachedform a 4 to 10 membered saturated or partially unsaturated heterocyclicring which may include 1 to 3 additional heteroatoms, in addition to thenitrogen atom to which said R^(a) and R^(b) are attached, selected fromN, O and S;

R^(d) and R^(h) are independently trifluoromethyl, alkyl, saturated orpartially unsaturated cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl orheterocyclylalkyl;

R^(e) is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturatedor partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, saturated or partially unsaturatedheterocycloalkyl or heterocyclylalkyl; and

Z is alkylene having from 1 to 6 carbons, or alkenylene or alkynyleneeach having from 2 to 6 carbons, wherein said alkylene, alkenylene andalkynylene are optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl.

In certain embodiments of a compound of Formula I, Ar¹ is a substitutedor unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. Inparticular embodiments, Ar¹ is optionally substituted with one or moregroups independently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b),NO₂, CN, C(═O)OR^(a), alkyl, and CF₃.

In certain embodiments of a compound of Formula I, Ar² is a substitutedor unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. Inparticular embodiments, said Ar² is optionally substituted with one ormore groups independently selected from F, Cl, Br, I, OR^(a),NR^(a)R^(b), NO₂, CN, C(═O)OH, alkyl, and CF₃.

In certain embodiments of a compound of Formula I, R is Z—NR²R³ or Z—OH.In certain embodiments, R² and R³ are independently selected from H,alkyl, saturated or unsaturated cycloalkyl, SO₂Me, C(═O)alkyl, an aminoacid, and a dipeptide, wherein said alkyl and cycloalkyl portions areoptionally substituted. In certain embodiments of a compound of FormulaI, Z is substituted or unsubstituted alkylene. In certain embodiments, Zis substituted or unsubstituted propylene.

In certain embodiments, R¹ is alkyl, cycloalkyl, heterocycloalkyl,O-alkyl, OR^(a), aryl, heteroaryl, CR^(b)(═NOR^(c)), or C(═O)R^(a),wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroarylare optionally substituted with one or more groups independentlyselected from OR^(a), NR^(a)R^(b), halogen, cycloalkyl, alkyl, aryl andCF₃. In certain embodiments, R^(a) is alkyl, cycloalkyl, aryl,heteroaryl or CF₃, wherein said alkyl, cycloalkyl, aryl, and heteroarylare optionally substituted with one or more groups selected from OR^(e),C(═O)R^(e), alkyl, or aryl.

In certain embodiments, R¹ is NR⁴R⁵. In certain embodiments, R⁴ and R⁵are independently selected from H, alkyl, saturated or partiallyunsaturated cycloalkyl, and heteroaryl.

Another aspect of this invention relates to compounds of the generalFormula II:

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts thereof, wherein R, R¹,Ar¹ and Ar² are as defined above.

In certain embodiments of a compound of Formula II, Ar¹ is a substitutedor unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. Incertain embodiments, Ar¹ is optionally substituted with one or moregroups independently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b),NO₂, CN, C(═O)OH, alkyl and CF₃.

In certain embodiments of a compound of Formula II, Ar² is a substitutedor unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. Incertain embodiments, said Ar² is optionally substituted with one or moregroups independently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b),NO₂, CN, C(═O)OH, alkyl, and CF₃.

In certain embodiments of a compound of Formula II, R is Z—NR²R³ orZ—OH. In certain embodiments, R² and R³ are independently selected fromH, alkyl, saturated or unsaturated cycloalkyl, SO₂Me, C(═O)alkyl, anamino acid, and a dipeptide, wherein said alkyl and cycloalkyl portionsare optionally substituted. In certain embodiments of a compound ofFormula II, Z is substituted or unsubstituted alkylene. In certainembodiments, Z is substituted or unsubstituted propylene.

In certain embodiments, R¹ is alkyl, cycloalkyl, heterocycloalkyl,O-alkyl, OR^(a), aryl, heteroaryl, CR^(b)(═NOR^(c)), or C(═O)R^(a),wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroarylare optionally substituted with one or more groups independentlyselected from OR^(a), NR^(a)R^(b), halogen, cycloalkyl, alkyl, aryl andCF₃. In certain embodiments, R^(a) is alkyl, cycloalkyl, aryl,heteroaryl or CF₃, wherein said alkyl, cycloalkyl, aryl, and heteroarylare optionally substituted with one or more groups selected from OR^(e),C(═O)R^(e), alkyl, or aryl.

In certain embodiments, R¹ is NR⁴R⁵. In certain embodiments, R⁴ and R⁵are independently selected from H, alkyl, saturated or partiallyunsaturated cycloalkyl, and heteroaryl.

Yet another aspect of this invention provides a compound of Formula III

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts thereof, wherein R, R¹,Ar¹ and Ar² are as defined above.

In certain embodiments of a compound of Formula III, Ar¹ is asubstituted or unsubstituted phenyl, thienyl, imidazolyl, pyridyl orpyrazolyl. In particular embodiments, Ar¹ is optionally substituted withone or more groups independently selected from F, Cl, Br, I, OR^(a),NR^(a)R^(b), NO₂, CN, C(═O)OR^(a), alkyl, and CF₃.

In certain embodiments of a compound of Formula III, Ar² is asubstituted or unsubstituted phenyl, thienyl, imidazolyl, pyridyl orpyrazolyl. In particular embodiments, said Ar² is optionally substitutedwith one or more groups independently selected from F, Cl, Br, I,OR^(a), NR^(a)R^(b), NO₂, CN, C(═O)OH, alkyl, and CF₃.

In certain embodiments of a compound of Formula III, R is Z—NR²R³ orZ—OH. In certain embodiments, R² and R³ are independently selected fromH, alkyl, saturated or unsaturated cycloalkyl, SO₂Me, C(═O)alkyl, anamino acid, and a dipeptide, wherein said alkyl and cycloalkyl portionsare optionally substituted. In certain embodiments of a compound ofFormula III, Z is substituted or unsubstituted alkylene. In certainembodiments, Z is substituted or unsubstituted propylene.

In certain embodiments, R¹ is alkyl, cycloalkyl, heterocycloalkyl,O-alkyl, OR^(a), aryl, heteroaryl, CR^(b)(═NOR^(c)), or C(═O)R^(a),wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroarylare optionally substituted with one or more groups independentlyselected from OR^(a), NR^(a)R^(b), halogen, cycloalkyl, alkyl, aryl andCF₃. In certain embodiments, R^(a) is alkyl, cycloalkyl, aryl,heteroaryl or CF₃, wherein said alkyl, cycloalkyl, aryl, and heteroarylare optionally substituted with one or more groups selected from OR^(e),C(═O)R^(e), alkyl, or aryl.

In certain embodiments, R¹ is NR⁴R⁵. In certain embodiments, R⁴ and R⁵are independently selected from H, alkyl, saturated or partiallyunsaturated cycloalkyl, and heteroaryl.

Another aspect of this invention provides a compound of Formula IV

and metabolites, solvates, resolved enantiomers, diastereomers, racemicmixtures and pharmaceutically acceptable salts thereof, wherein R, Ar¹and Ar² are as defined above, and

R^(x) and R^(y) are independently H, alkyl, saturated or partiallyunsaturated cycloalkyl or aryl, wherein said alkyl, cycloalkyl and arylare optionally substituted with one or more groups independentlyselected from oxo (with the proviso that it is not substituted on saidaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d),—NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl,

or R^(x) and R^(y) together with the atom to which they are attachedform a saturated or partially unsaturated carbocyclic ring orheterocyclic ring having one or more heteroatoms independently selectedfrom N, O and S, wherein said carbocyclic and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl;

and R^(a), R^(b), R^(c) and R^(d) are as defined above,

or R^(a) and R^(x) together with the atoms to which they are attachedform a saturated or partially unsaturated heterocyclic ring which mayinclude 1 to 3 additional heteroatoms, in addition to the oxygen atom towhich said R^(a) is attached, selected from N, O and S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(h), —NR^(f)SO₂R^(h),—SO₂NR^(e)R^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—NR^(f)C(═O)OR^(h), —NR^(f)C(═O)R^(e), —C(═O)NR^(e)R^(f), —NR^(e)R^(f),—NR^(g)C(═O)NR^(e)R^(f), —NR^(c)C(NCN)NR^(e)R^(f), —OR^(e), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl, wherein R^(e),R^(f), R^(g) and R^(h) are as defined above.

In certain embodiments of a compound of Formula IV, at least one ofR^(x) and R^(y) is not H. In certain embodiments, R^(a) is H or alkyl.In particular embodiments, R^(x) and R^(a) are alkyl.

In certain embodiments of a compound of Formula IV, Ar¹ is a substitutedor unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. Inparticular embodiments, Ar¹ is optionally substituted with one or moregroups independently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b),NO₂, CN, C(═O)OR^(a), alkyl, and CF₃.

In certain embodiments of a compound of Formula IV, Ar² is a substitutedor unsubstituted phenyl, thienyl, imidazolyl, pyridyl or pyrazolyl. Inparticular embodiments, said Ar² is optionally substituted with one ormore groups independently selected from F, Cl, Br, I, OR^(a),NR^(a)R^(b), NO₂, CN, C(═O)OH, alkyl, and CF₃.

In certain embodiments of a compound of Formula IV, R is Z—NR²R³ orZ—OH. In certain embodiments, R² and R³ are independently selected fromH, alkyl, saturated or unsaturated cycloalkyl, SO₂Me, C(═O)alkyl, anamino acid, and a dipeptide, wherein said alkyl and cycloalkyl portionsare optionally substituted. In certain embodiments of a compound ofFormula IV, Z is substituted or unsubstituted alkylene. In certainembodiments, Z is substituted or unsubstituted propylene.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical having one to ten carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described herein. Examplesof alkyl radicals include C₁-C₁₂ hydrocarbon moieties such as: methyl(Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, and1-octyl.

The term “alkylene” as used herein refers to a linear or branchedsaturated divalent hydrocarbon radical of one to twelve carbon atoms,e.g., methylene (—CH₂—), 1,2-ethylene (—CH₂CH₂—)_(,) 1,3-propylene(—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), and the like, optionallysubstituted independently with one or more substituents describedherein.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical having two to 10 carbon atoms and at least onedouble bond, and include, but is not limited to, ethenyl, propenyl,1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.The term “alkenyl” includes allyl.

The term “allyl” refers to a radical having the formula RCC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, wherein the allyl may be optionally substitutedindependently with one or more substituents described herein.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical of two to twelve carbons containing at least onedouble bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, ethenylene (—CH═CH—),propenylene (—CH═CHCH₂—), and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms containing at least one triplebond. Examples include, but are not limited to, ethynyl, propynyl,butynyl, pentyn-2-yl and the like, wherein the alkynyl radical may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical of two to twelve carbons containing at least onetriple bond, wherein the alkynylene radical may be optionallysubstituted independently with one or more substituents describedherein. Alkynylene radicals include, but are not limited to: acetylene(—C≡C—), propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡C—).

The terms “cycloalkyl,” “carbocycle,” and “carbocyclyl” are usedinterchangeably herein and refer to saturated or partially unsaturated(i.e., having one or more double and/or triple bonds within thecarbocycle) cyclic hydrocarbon radical having from three to twelvecarbon atoms. The term “cycloalkyl” includes monocyclic and polycyclic(e.g., bicyclic and tricyclic) cycloalkyl structures, wherein thepolycyclic structures optionally include a saturated or partiallyunsaturated cycloalkyl fused to a saturated or partially unsaturatedcycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike. Bicyclic carbocycles have 7 to 12 ring atoms, e.g. arranged as abicyclo[4,5], [5,5], [5,6] or [6,6] system, or as bridged systems suchas bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, andbicyclo[3.2.2]nonane. The cycloalkyl may be optionally substitutedindependently at one or more substitutable positions with one or moresubstituents described herein. Such cycloalkyl groups may be optionallysubstituted with, for example, one or more groups independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl and di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “heteroalkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals.

The terms “heterocycloalkyl,” “heterocycle” and “heterocyclyl” are usedinterchangeably herein and refer to a saturated or partially unsaturated(i.e., having one or more double and/or triple bonds within thecarbocycle) carbocyclic radical of 3 to 8 ring atoms in which at leastone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur,the remaining ring atoms being C, where one or more ring atoms may beoptionally substituted independently with one or more substituentsdescribed below. The radical may be a carbon radical or heteroatomradical. The term “heterocycle” includes heterocycloalkoxy.“Heterocycloalkyl” also includes radicals where heterocycle radicals arefused with a carbocyclic, heterocyclic, aromatic or heteroaromatic ring.Examples of heterocycloalkyl rings include, but are not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thietanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas.Spiro moieties are also included within the scope of this definition.The heterocycle may be C-attached or N-attached where such is possible.For instance, a group derived from pyrrole may be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached). Further, a group derived fromimidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl(C-attached). An example of a heterocyclic group wherein 2 ring carbonatoms are substituted with oxo (═O) moieties is1,1-dioxo-thiomorpholinyl. The heterocycle groups herein areunsubstituted or substituted in one or more substitutable positions withvarious groups.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Further examples of carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

The term “aryl” refers to a monovalent aromatic carbocyclic radicalhaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, etc.), which is optionallysubstituted independently with one or more substituents describedherein.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings and includes fused ring systems (at least one ofwhich is aromatic) of 5-10 atoms containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur. Examples of heteroarylgroups are pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. Spiro moieties are also included within the scope of thisdefinition. Heteroaryl groups are optionally substituted independentlywith one or more substituents described herein.

The term “halogen” represents fluorine, bromine, chlorine, and iodine.

The term “arylalkyl” means an alkyl moiety (as defined above)substituted with one or more aryl moiety (also as defined above).Examples include, but are not limited to, aryl-C₁₋₃-alkyls such asbenzyl, phenylethyl, and the like. The arylalkyl, may be optionallysubstituted independently with one or more substituents describedherein.

The term “heteroarylalkyl” means an alkyl moiety (as defined above)substituted with a heteroaryl moiety (also as defined above). Examplesinclude, but are not limited to, 5- or 6-membered heteroaryl-C₁₋₃-alkylssuch as oxazolylmethyl, pyridylethyl and the like. The heteroarylalkylmay be optionally substituted independently with one or moresubstituents described herein.

The term “heterocyclylalkyl” means an alkyl moiety (as defined above)substituted with a heterocyclyl moiety (also defined above). Examplesinclude, but are not limited to, 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls such as tetrahydropyranylmethyl. Theheterocyclylalkyl may be optionally substituted independently with oneor more substituents described herein.

The term “cycloalkylalkyl” means an alkyl moiety (as defined above)substituted with a cycloalkyl moiety (also defined above). Examplesinclude 5- or 6-membered cycloalkyl-C₁₋₃-alkyls such ascyclopropylmethyl. The cycloalkylalkyl may be optionally substitutedindependently with one or more substituents described herein.

The term “amino acid” includes residues of natural amino acids (e.g.,Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, H is, Hyl, Hyp, Ile, Leu, Lys,Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val) in D or L form, as well asunnatural amino acids (such as, but not limited to, phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine).An amino acid can be linked to the remainder of a compound of FormulaI-IV through the carboxy terminus, the amino terminus, or through anyother convenient point of attachment, such as, for example, through thesulfur of cysteine. In a particular embodiment, the amino acid is linkedto the remainder of a compound of Formula I-IV through the carboxyterminus.

In general, the various moieties or functional groups of the compoundsof Formulas I-IV may be optionally and independently substituted by oneor more substituents. Examples of substituents suitable for purposes ofthis invention include, but are not limited to, oxo, halogen, cyano,nitro, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —NR″SO₂R′, —SO₂NR′R″, —C(═O)R′, —C(═O)OR′,—OC(═O)R′, —NR″C(═O)OR′, —NR″C(═O)R′, —C(═O)NR′R″, —NR′R″,—NR′″C(═O)N′R″, —OR′, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl, where R′, R″ and R′″ are independently H, alkyl,alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturatedcycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl,or heteroaryl.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, an arylalkyl radical is attached to the structure inquestion by the alkyl group.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures, pure diastereomers and pure enantiomers of the compounds ofFormulas I-IV.

The term “enantiomer” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. The term“diastereomer” refers to a pair of optical isomers which are not mirrorimages of one another. Diastereomers have different physical properties,e.g. melting points, boiling points, spectral properties, andreactivities.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

In addition to compounds of Formulas I-IV, the invention also includessolvates, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable salts of such compounds. The phrase “pharmaceuticallyacceptable” indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, and/or the mammal being treated therewith.

The term “solvate” refers to an aggregate of a molecule with one or moresolvent molecules.

A “pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of a compound of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes phosphoserine, phosphothreonine,phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylicacid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.Particular examples of prodrugs of this invention include a compound ofFormula I-IV covalently joined to a phosphate residue or a valineresidue.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. As anotherexample, compounds of this invention comprising free hydroxy groups maybe derivatized as prodrugs by converting the hydroxy group into groupssuch as, but not limited to, phosphate ester, hemisuccinate,dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl groups, asoutlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers wherein the acyl group may be an alkyl ester, optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., 1996, 39, 10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

Free amines of compounds of this invention can also be derivatized asamides, sulfonamides or phosphonamides. All of these prodrug moietiesmay incorporate groups including, but not limited to, ether, amine andcarboxylic acid functionalities. For example, a prodrug can be formed bythe replacement of a hydrogen atom in the amine group with a group suchas R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl isa natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl,—C(OH)C(O)OY wherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ whereinY₀ is (C₁-C₄)alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N— or di-N,N—(C₁-C₆)alkylamino alkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N— or di-N,N—(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference. Prodrugs of acompound may be identified using routine techniques known in the art.

A “pharmaceutically acceptable salt,” unless otherwise indicated,includes salts that retain the biological effectiveness of the freeacids and bases of the specified compound and that are not biologicallyor otherwise undesirable. A compound of the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organic basesor acids to form a pharmaceutically acceptable salt. Examples ofpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates. Since a single compound of thepresent invention may include more than one acidic or basic moiety, thecompounds of the present invention may include mono, di or tri-salts ina single compound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,for example an inorganic acid such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid such as glucuronicacid or galacturonic acid, an alpha hydroxy acid such as citric acid ortartaric acid, an amino acid such as aspartic acid or glutamic acid, anaromatic acid such as benzoic acid or cinnamic acid, a sulfonic acidsuch as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Examplesof suitable inorganic salts include those formed with alkali andalkaline earth metals such as lithium, sodium, potassium, barium andcalcium. Examples of suitable organic base salts include, for example,ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium,bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine,dibenzyl-ethylenediamine, and the like salts. Other salts of acidicmoieties may include, for example, those salts formed with procaine,quinine and N-methylglucosamine, plus salts formed with basic aminoacids such as glycine, ornithine, histidine, phenylglycine, lysine andarginine.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. All isotopes of any particular atom or elementas specified is contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

Also falling within the scope of this invention are metabolites ofcompounds of Formulas I-IV. A “metabolite” is a pharmacologically activeproduct produced through metabolism in the body of a specified compoundor salt thereof. Metabolites may result, for example, from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound. Accordingly, the invention includesmetabolites of compounds of Formulas I-IV, including compounds producedby a process comprising contacting a compound of this invention with amammal for a period of time sufficient to yield a metabolic productthereof.

Metabolites typically are identified by preparing a radiolabelled (e.g.,¹⁴C or ³H) isotope of a compound of the invention, administering itparenterally in a detectable dose (e.g., greater than about 0.5 mg/kg)to an animal such as rat, mouse, guinea pig, monkey, or to a human,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. Metabolites, so long as they are not otherwisefound in vivo, are useful in diagnostic assays for therapeutic dosing ofthe compounds of the invention.

The inventive compounds may be prepared using the reaction routes andsynthesis schemes as described below, employing the techniques availablein the art using starting materials that are readily available or can besynthesized using methods known in the art. Illustrations of thepreparation of certain compounds of the present invention are shown inSchemes I-III below.

Scheme I illustrates a method of preparing compounds of Formula I-6.Acid I-1 can be coupled with tert-butyl carbazate using standardcoupling procedures including, but not limited to, EDCI/HOBt, PyBOP, orDIC to produce intermediate I-2. Removal of the tert-butoxycarbonyl(Boc) group of I-2 can be achieved by treatment with a variety of acidsincluding, but not limited to, TFA and HCl/dioxane to give acidhydrazide I-3. I-3 can then be condensed with ketone I-4 to provideintermediate I-5 utilizing a variety of acid catalysts. In oneembodiment, compounds I-3 and I-4 are combined in ethanol with addedacetic acid and heated at elevated temperature (95° C.) to providecompound I-5. Oxadiazolines I-6 can be prepared by combining I-5 withthe appropriate anhydride or acid chloride or carboxylic acid in thepresence of a standard coupling agent. For example, oxadiazoline I-6 canbe prepared by treatment with excess anhydride at elevated temperaturesin an appropriate organic solvent such as DCE. Alternatively, treatmentof I-5 with acid chloride and an appropriate base, such as pyridine orEt₃N, in a variety of organic solvents such as DCM or DCE at roomtemperature affords oxadiazoline I-6. Alternatively, I-6 can be preparedthrough coupling with anhydrides, or through treatment of I-5 with theappropriate carboxylic acid and Ac₂O in DCE at elevated temperature (80°C.). Oxadiazoline I-6 can be obtained by treatment of I-5 with acarboxylic acid and amide-coupling reagent, including but not limited toEDCI/HOBT or diethyl cyanophosphonate, and appropriate base, Et₃N orDIEA, in a suitable organic solvent such as DCM, DCE, DMF, THF, orsolvent mixture at room temperature or above. In certain embodiments,this coupling is accomplished with diethyl cyanophosphonate and TEA inDCE at elevated temperature (80° C.) to provide I-6.

Scheme II illustrates a method of preparing thiodiazolines of FormulasII-3, I-4, II-5, II-6 and II-7. Thiohydrazide II-1 (Takasugi, J. J.;Buckwalter, B. L., EP Patent No. 1004241) can be condensed with ketoneII-2 in an appropriate organic solvent such as ethanol to givethiodiazoline II-3. In certain embodiments, the condensation can becatalyzed by acetic acid. Thiodiazoline II-3 can be functionalized toproduce II-4 by standard coupling procedures including, but not limitedto, EDCI/HOBt, PyBOP, HATU, or DIC and the appropriate carboxylic acid.Alternatively, compound II-4 can be prepared by treatment of II-3 withthe appropriate acid chloride and amine base in a suitable organicsolvent such as THF. A compound of formula II-5 can be prepared byreacting compound II-3 with the appropriate carbamyl chloride in thepresence of an amine base. Alternatively, a compound of formula II-5 canbe prepared by treatment of a compound of formula II-3 with theappropriate isocyanate in an appropriate organic solvent such as THF.Another method for preparing compound II-5 comprises subjecting theappropriate amine to a carbonylating reagent such as, but not limitedto, triphosgene, diphosgene, phosgene or carbonyldiimidazole, followedby treatment with II-3. In certain embodiments, the amine can be treatedwith triphosgene, Et₃N and catalytic DMAP followed by II-3 to give II-5.Similarly, compounds of formula II-6 can be prepared by subjecting II-3to a chloroformate in the presence of an amine base. Chloroformates canbe prepared by subjecting alcohols to a carbonylating reagent, asdescribed above. Alternatively, compounds of formulae II-5, II-6 andII-7 can be prepared by treating II-3 with carbonyldiimidazole followedby addition of MeI to generate the stable methylimidazolium iodide salt.Addition of an amine, alcohol, hydroxylamine or alkoxylamine in thepresence of Et₃N to the methylimidazolium iodide salt generates theanalogs of formulae II-5, II-6, and II-7, respectively. Derivatives offormulae II-5, II-6 and II-7 can be prepared from an intermediate4-nitrophenyl carboxylate. Thiadiazoline II-3 can be treated with4-nitrophenylchloroformate in the presence of a suitable base such asDIEA or Et₃N in a suitable organic solvent such as DCE or DCM at roomtemperature. Addition of amine, alcohol, hydroxylamine or alkoxyl aminein the presence of a suitable base such as DIEA or Et₃N to the4-nitrophenyl carboxylate in a suitable organic solvent such as DCE orTHF at elevated temperature affords the analogs of formulae II-5, II-6,and II-7, respectively.

In the above Schemes any of the substituents R, R¹, Ar¹, Ar², maycontain functional groups that require protection in the reactionsequences described. The choice of protecting group and the deprotectionconditions will depend on the functional group and is well known tothose skilled in the art. Examples of use of protecting groups aredescribed in Scheme III. These examples are representative only are notmeant to limit the scope of this application in any way.

Scheme III shows a method of preparing compounds of Formulas III-4,III-5 and III-6. Compounds III-1 and III-2 can be prepared as describedin Schemes I and II using the appropriate ketone containing an aminogroup either masked as an azide or protected as a t-butyl carbamate.Amine III-3 can be generated from azide III-1 by a variety of methodsincluding, but not limited to, Staudinger reaction with Ph₃P/water andhydrogenation in the presence of Pd/C under 1 atm H₂. Amine III-3 canalso be prepared from t-butyl carbamate III-2 by standard acidicdeprotection conditions including but not limited to TFA in DCM, HCl ina suitable organic solvent such as dioxane or diethyl ether, and neatformic acid. Once unmasked amine III-3 can be further functionalized.Derivatives III-4, wherein R² and R³ are independently selected fromalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynylgroups, can be made using standard reductive amination conditions. Theseconditions include but are not limited to treatment of amine III-3 withthe appropriate aldehyde or ketone in the presence of dehydrating agentssuch as MgSO₄ followed by reduction with NaBH₄, Na(OAc)₃BH or NaCNBH₃ ina suitable organic solvent such as DCM, DCE, acetonitrile or THF.Alternatively, amine III-3 can be treated with the appropriate aldehydeor ketone in the presence of acetic acid and reducing agent such asNa(OAc)₃BH or NaCNBH₃ in suitable organic solvents such as DCM, DCE,acetonitrile or THF. In certain embodiments, III-3 and the appropriatealdehyde or ketone are combined in acetonitrile and stirred for 1 hour.Acetic acid and Na(OAc)₃BH are then added and the reaction mixture isheated at an elevated temperature (45° C.) to afford III-4. AnalogsIII-4 where R² or R³ is —C(═O)R⁶, —SO₂R⁶, —C(═O)NR⁴R⁵, —SO₂NR⁴R⁵, aminoacid, or polypeptide can be prepared by standard methods known to thoseskilled in the art. These include but are not limited to treatment ofamine III-3 with acid chloride, sulfamoyl chloride, sulfonyl chloride orisocyanate in the presence or absence of tertiary amine base, andtreatment of III-3 with carboxylic acid, amino acid or polypeptide inthe presence of standard coupling reagents including, but not limitedto, EDCI/HOBt, PyBOP, HATU, or DIC. Derivatives of the formula III-5 mayalso be prepared by subjecting III-2 to a base such as NaH, KH, LiHMDS,NaHMDS, KHMDS or other suitable base and an appropriate alkylating agentwhich may include, but is not limited to, alkyl halides, (un)substitutedbenzyl halides, (un)substituted allyl halides, (un)substituted propargylhalides, sulfonate esters and sulfate esters in a suitable solvent suchas DMF or THF to afford III-5. III-6 can be prepared from III-5 bystandard acidic deprotection conditions including, but not limited to,TFA in DCM, HCl in a suitable organic solvent such as dioxane or diethylether, and neat formic acid. In certain embodiments, III-2 is treatedwith NaH in DMF followed by iodomethane to afford III-5 wherein R² ismethyl. Removal of the BOC group is can be achieved, for example, withTFA in DCM to provide III-6. Alternatively, III-6 can be generated fromIII-3 by treatment with a suitable alkylating agent and a suitable basewhich may include, but is not limited to, a tertiary amine, K₂CO₃,Na₂CO₃, Cs₂CO₃, or CsOH in an appropriate solvent such as acetonitrile,DMF or THF to afford III-6.

In any of the synthetic methods for preparing compounds of Formula I-IV,it may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified to the desired degree ofhomogeneity by the techniques common in the art. Typically suchseparations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example: reverse-phase and normal phase; size exclusion;ion exchange; high, medium and low pressure liquid chromatographymethods and apparatus; small scale analytical; simulated moving bed(SMB) and preparative thin or thick layer chromatography, as well astechniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a reactionmixture with a reagent selected to bind to or render otherwise separablea desired product, unreacted starting material, reaction by product, orthe like. Such reagents include adsorbents or absorbents such asactivated carbon, molecular sieves, ion exchange media, or the like.Alternatively, the reagents can be acids in the case of a basicmaterial, bases in the case of an acidic material, binding reagents suchas antibodies, binding proteins, selective chelators such as crownethers, liquid/liquid ion extraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., (1975), 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−)menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.,(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

The compounds of the invention find use in a variety of applications.According to certain embodiments, this invention provides methods ofblocking or inhibiting mitosis by administering an effective amount of acompound of Formula I-IV. As will be appreciated by those skilled in theart, mitosis may be altered in a variety of ways; that is, one canaffect mitosis either by increasing or decreasing the activity of acomponent in the mitotic pathway. Stated differently, mitosis may beaffected (e.g., disrupted) by disturbing equilibrium, either byinhibiting or activating certain components using the compounds of thepresent invention, for example, by modulating spindle function orblocking mitotic kinesin. Similar approaches may be used to altermeiosis.

In certain embodiments, the compounds of the invention can be used tomodulate mitotic spindle formation, thus causing prolonged cell cyclearrest in mitosis. By “modulate” herein is meant altering mitoticspindle formation, including increasing and decreasing spindleformation. By “mitotic spindle formation” herein is meant organizationof microtubules into bipolar structures by mitotic kinesins. By “mitoticspindle dysfunction” herein is meant mitotic arrest and monopolarspindle formation.

In certain embodiments, the compounds of the invention can be used tobind to and/or modulate the activity of a mitotic kinesin. In anembodiment, the mitotic kinesin is a member of the bimC subfamily ofmitotic kinesins as described in U.S. Pat. No. 6,284,480, which isincorporated herein by reference. In a further embodiment, the mitotickinesin is human KSP, although the activity of mitotic kinesins fromother organisms may also be modulated by the compounds of the presentinvention. In this context, modulate means either increasing ordecreasing spindle pole separation, causing malformation, i.e.,splaying, of mitotic spindle poles, or otherwise causing morphologicalperturbation of the mitotic spindle. Also included within the definitionof KSP for these purposes are variants and/or fragments of KSP. Inaddition, other mitotic kinesins may be inhibited by the compounds ofthe present invention.

In certain embodiments, the compounds of the invention can be used totreat abnormal or unwanted cell growth conditions, such as, but notlimited to, cellular proliferative diseases, for example, cancer,hyperplasias, restenosis, cardiac hypertrophy, immune disorders,infectious disease, fungal or other eukaryote infections, inflammatorydiseases, arthritis, graft rejection, inflammatory bowel disease,proliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like, by administering atherapeutically effective amount of a compound of Formula I-IV, or apharmaceutically acceptable salt, prodrug, metabolite or solvatethereof.

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application and, unless otherwiseindicated, refer to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). Examples of abnormal cellgrowth conditions include, but are not limited to, cancer, autoimmunedisease, arthritis, graft rejection, inflammatory bowel disease, orproliferation induced after a medical procedure.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

It is appreciated that in some cases the cells may not be in a hyper- orhypoproliferation state (abnormal state) but still require treatment.For example, during wound healing, the cells may be proliferating“normally”, but proliferation enhancement may be desired. Similarly, asdiscussed above, in the agriculture arena, cells may be in a “normal”state, but proliferation modulation may be desired to enhance a crop bydirectly enhancing growth of a crop, or by inhibiting the growth of aplant or organism which adversely affects the crop. Thus, in certainembodiments, the invention herein includes application to cells orindividuals that are afflicted or may eventually become afflicted withany one of these disorders or states.

The invention also provides a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite or solvatethereof, and a pharmaceutically acceptable carrier. In certainembodiments, the invention provides a pharmaceutical composition for thetreatment of solid tumors such as skin, breast, brain, cervicalcarcinomas, testicular carcinomas, etc. More particularly, cancers thatmay be treated by the compositions and methods of the invention include,but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. The term “cancerous cell” as providedherein, includes a cell afflicted by any one of the above identifiedconditions.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite or solvatethereof. In certain embodiments, said method relates to the treatment ofcancers, including the above identified conditions.

The invention also relates to a composition for the treatment of ahyperproliferative disorder in a mammal, comprising a therapeuticallyeffective amount of a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite or solvatethereof, in combination with an anti-tumor agent selected from mitoticinhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA,intercalating antibiotics, growth factor inhibitors, signal transductioninhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptormodulators, proteasome inhibitors, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors,anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, andprenyl-protein transferase inhibitors.

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite or solvate thereof, in combination with an anti-tumor agentselected from mitotic inhibitors, alkylating agents, anti-metabolites,antisense DNA or RNA, intercalating antibiotics, growth factorinhibitors, signal transduction inhibitors, cell cycle inhibitors,enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, anti-androgens, targeted antibodies, HMG-CoAreductase inhibitors, and prenyl-protein transferase inhibitors.

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention, or a pharmaceutically acceptablesalt, solvate, metabolite or prodrug thereof, in combination with anamount of a chemotherapeutic, wherein the amounts of the compound, salt,solvate, or prodrug, and of the chemotherapeutic are together effectivein inhibiting abnormal cell growth. Many chemotherapeutics are known inthe art. In certain embodiments, the chemotherapeutic is selected frommitotic inhibitors, alkylating agents, anti-metabolites, antisense DNAor RNA, intercalating antibiotics, growth factor inhibitors, signaltransduction inhibitors, cell cycle inhibitors, enzyme inhibitors,retinoid receptor modulators, proteasome inhibitors, topoisomeraseinhibitors, biological response modifiers, anti-hormones, angiogenesisinhibitors, anti-androgens, targeted antibodies, HMG-CoA reductaseinhibitors, and/or prenyl-protein transferase inhibitors.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder whichmethod comprises administering to the mammal an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt, metabolitesolvate or prodrug thereof, in combination with radiation therapy,wherein the amounts of the compound, salt, solvate, or prodrug, incombination with the radiation therapy is effective in inhibitingabnormal cell growth or treating the hyperproliferative disorder in themammal. Techniques for administering radiation therapy are known in theart, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation, which comprises administering tothe mammal an amount of a compound of the present invention or apharmaceutically acceptable salt, solvate, metabolite or prodrugthereof, which amount is effective in sensitizing abnormal cells toradiation treatment. The amount of the compound, salt, solvate,metabolite or prodrug to be used in this method can be determinedaccording to means for ascertaining effective amounts of such compoundsas described herein or by methods know to those skilled in the art.

The invention also provides pharmaceutical compositions and methods ofuse thereof for inhibiting abnormal cell growth in a mammal, comprisingadministering to a mammal in need thereof an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, solvate,metabolite, or prodrug thereof, and an amount of one or more substancesselected from anti-angiogenesis agents, signal transduction inhibitors,and antiproliferative agents, in amounts effective to inhibit abnormalcell growth.

For example, anti-angiogenesis agents, such as MMP-2(matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used inconjunction with a compound or pharmaceutical compositions of thepresent invention. Examples of useful COX-II inhibitors includeCELEBREX™ (alecoxib) BEXTRA® (valdecoxib), Arcoxia™ (etoricoxib),Prexige® (lumiracoxib) and Vioxx® (rofecoxib). Examples of MMP-2 andMMP-9 inhibitors are those that have little or no activity inhibitingMMP-1, and include those that selectively inhibit MMP-2 and/or MMP-9relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

The invention also relates to a composition for the treatment ofunwanted cell growth, for example a fungal infection, in a mammal,comprising a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite or solvate thereof. In certain embodiments the compositionsof the present invention modulate the activity of the fungal members ofthe bimC kinesin subgroup, as is described in U.S. Pat. No. 6,284,480.

The invention also relates to a method of treating unwanted cell growth,for example a fungal infection, in a mammal, comprising administering atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite or solvatethereof.

The compounds of this invention may be used alone in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of KSP kinesin. For example, acompound of this invention may be applied in combination with one ormore other anti-tumor substances, including, but not limited to, mitoticinhibitors such as vinblastine; alkylating agents such as cis-platin,carboplatin and cyclophosphamide; anti-metabolites such as5-fluorouracil, cytosine arabinside and hydroxyurea; one of thepreferred anti-metabolites disclosed in European Patent Application No.239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; antisense RNA and DNA oligonucleotides such as G3139, ODN698, andGEM231; growth factor inhibitors; MEK inhibitors, signal transductioninhibitors, such as agents that can inhibit EGFR (epidermal growthfactor receptor) responses, such as EGRF antibodies, EGF antibodies andmolecules that are EGFR inhibitors such as the compounds ZD-1839(AstraZeneca) and BIBX-1382 (Boehringer Ingelheim); VEGF inhibitors suchas SU-6668 (Sugen, Inc., South San Francisco, Calif.) or the anti-VEGFmonoclonal antibody Avestin (Genentech, Inc., South San Francisco,Calif.); cell cycle inhibitors; intercalating antibiotics such asadriamycin and bleomycin; enzymes, for example, interferon; retinoidreceptor modulators such as bexarotene, ILX23-7553, andN-4-carboxyphenyl retinamide; proteasome inhibitors such as lactacystinand bortezomib; topoisomerase inhibitors such as topotecan, rebutecanand teniposide; anti-hormone such as anti-estrogens such as Nolvadex™(tamoxifen); anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide);monoclonal antibody targeted therapeutic agents which have cytotoxicagents or radioisotopes attached to a cancer cell specific or targetcell specific monoclonal antibody; inhibitors of HMG-CoA reductase(3-hydroxy-3-methylglutaryl-CoA reductase) such as simvastatin (ZOCOR®)and atorvastatin (LIPITOR®); prenyl-protein transferase inhibitors;inhibitors of protein kinases that transduce cell cycle checkpointsignals (e.g. ART, ARM, the Chk1 and Chk2 kinases, cdk and cdc kinase)such as 7-hydroxystaurosporin, flavopiridol and CYC202 (Cyclacel); andinhibitors of kinases involved in mitotic progression where such kinasesinclude, but are not limited to, Polo-like kinases and aurora kinase.Such conjoint treatment may be achieved by way of simultaneous,sequential or separate dosing of the individual components of treatment.

The compounds of the present invention may also be used in combinationwith other known inhibitors of mitotic kinesins. Examples of inhibitorsof mitotic kinesins, and in particular the human mitotic kinesin KSP,include inhibitors described in PCT Publications WO 01/30768, WO01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO03/049,678, WO 03/051854, WO 03/39460 WO 03/079,973, WO 03/088,903, WO03/094,839, WO 03/097,053, WO 03/099,211, WO 03/099,286, WO 03/103,575,WO 03/105,855, WO 03/106,426, WO 04/032,840, WO 04/034,879, WO04/037,171, WO 04/039,774, WO 04/055,008, WO 04/058,148, WO 04/058,700,WO 04/064,741, WO 04/092147, WO 04/111023, WO 04/111024, WO 05/035512,WO 05/017190, WO 05/018547, and WO 05/019206, which are specificallyincorporated herein by reference. Examples of such inhibitors include(2S)-4-(2,5-difluorophenyl)-N-[(3S,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;(2S)-4-(2,5-difluorophenyl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;(2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide,(2S)-4-(2,5-difluorophenyl)-N-[(2R,4R)-2-(fluoromethyl)-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide,and(2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide.

The compounds of the present invention may also be used in the treatmentof cancer in combination with compounds that are not anti-tumorcompounds. For example, a compound of this invention may be applied incombination with one or more substances, including, but not limited to,PPAR-γ and PPAR-δ agonists such as troglitazone, gene therapy agents,and inhibitors of inherent multidrug resistance (e.g. p-glycoproteininhibitors).

A compound of the present invention may also be employed in conjunctionwith anti-emetic agents to treat nausea or emesis, by way ofsimultaneous, sequential or separate dosing of the individual componentsof treatment.

A compound of the present invention may also be administered incombination with an agent useful in the treatment of anemia, such asepoetin alfa, by way of simultaneous, sequential or separate dosing ofthe individual components of treatment.

A compound of the present invention may also be administered incombination with an agent useful in the treatment of neutropenia, by wayof simultaneous, sequential or separate dosing of the individualcomponents of treatment. Such a neutropenia treatment agent is, forexample, a hematopoietic growth factor that regulates the production andfunction of neutrophils such as a human granulocyte colony stimulatingfactor, (G-CSF). An example of a G-CSF is filgrastim.

A compound of the present invention may also be administered incombination with an immunologic-enhancing drug, such as levamisole,isoprinosine and Zadaxin®, by way of simultaneous, sequential orseparate dosing of the individual components of treatment.

Further provided is a compound of Formula I-IV for use as a medicamentin the treatment of the diseases or conditions described above in awarm-blooded animal, such as a mammal, for example, a human, sufferingfrom such disease or condition. Also provided is the use of a compoundof Formula I-IV in the preparation of a medicament for the treatment ofthe diseases and conditions described above in a warm-blooded animal,such as a mammal, for example a human, suffering from such disorder.

The term “treating,” as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment,” as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. “Treating” is intended to meanat least the mitigation of a disease condition in a mammal, such as ahuman, and includes, but is not limited to, modulating and/or inhibitingthe disease condition, and/or alleviating the disease condition.

In treating a subject, it will be understood that the specific dosagelevel and frequency of dosage for any particular subject may be variedand will depend upon a variety of factors including the activity of thespecific compound of Formula I-IV, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition, but can nevertheless be routinely determined byone skilled in the art.

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeparenteral administration (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),e.g., by bolus injection or continuous infusion. Other suitable roundsinclude vaginal, intraperitoneal, intrapulmonary, oral, and intranasaladministration. Alternatively, the compounds of the invention may beadministered topically (e.g., to the skin) for the treatment of atopical condition such as a fungal skin infection. It will beappreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound is administered orally,it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound isadministered parenterally, it may be formulated with a pharmaceuticallyacceptable parenteral vehicle and in a unit dosage injectable form, asdetailed below.

In order to use a compound of Formula I-IV or a pharmaceuticallyacceptable salt, solvate, metabolite or prodrug thereof for thetherapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition that comprises a compound of the Formula I-IV, or apharmaceutically acceptable salt, solvate, metabolite or prodrugthereof, in association with a pharmaceutically acceptable diluent orcarrier.

To prepare the pharmaceutical compositions according to this invention,a therapeutically or prophylactically effective amount of a compound ofFormula I-IV or pharmaceutically acceptable salt, solvate, metabolite orprodrug thereof (alone or together with an additional therapeutic agentas disclosed herein) is intimately admixed, for example, with apharmaceutically acceptable carrier according to conventionalpharmaceutical compounding techniques to produce a dose. A carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral. Examples ofsuitable carriers include any and all solvents, dispersion media,adjuvants, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, sweeteners, stabilizers (to promote longterm storage), emulsifiers, binding agents, thickening agents, salts,preservatives, solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, flavoringagents, and miscellaneous materials such as buffers and absorbents thatmay be needed in order to prepare a particular therapeutic composition.The use of such media and agents with pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with a compound of Formula I-IV, its use in thetherapeutic compositions and preparations is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions andpreparations as described herein.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above.This suspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,3-butanediol orprepared as a lyophilized powder. Among the acceptable vehicles andsolvents that may be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile fixed oils mayconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid may likewisebe used in the preparation of injectables. Injectable solutions ormicroemulsions may be introduced into a patient's blood stream by localbolus injection. Alternatively, it may be advantageous to administer thesolution or microemulsion in such a way as to maintain a constantcirculating concentration of the instant compound. In order to maintainsuch a constant concentration, a continuous intravenous delivery devicemay be utilized. An example of such a device is the DeltecCADD-PLUS™model 5400 intravenous pump.

The compositions of the invention may also be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous, orintramuscular dosing or as a suppository for rectal dosing). Forexample, compositions intended for oral use may contain, for example,one or more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, esters or partial esters derived from fatty acids and hexitolanhydrides (for example sorbitan monooleate) and condensation productsof the said partial esters with ethylene oxide such as polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening,flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

Compositions for transdermal administration may be in the form of thosetransdermal skin patches that are well known to those of ordinary skillin the art.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990, which is specifically incorporated hereinby reference.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. In certain embodiments,a suitable amount of a compound of Formula I-IV is administered to amammal undergoing treatment for cancer. Administration in certainembodiments occurs in an amount between about 0.001 mg/kg of body weightto about 60 mg/kg of body weight per day. In another embodiment,administration occurs in an amount between 0.5 mg/kg of body weight toabout 40 mg/kg of body weight per day. In some instances, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate,while in other cases still larger doses may be employed without causingany harmful side effect, provided that such larger doses are firstdivided into several small doses for administration throughout the day.For further information on routes of administration and dosage regimes,see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry(Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, whichis specifically incorporated herein by reference.

The size of the dose for therapeutic or prophylactic purposes of acompound of Formula I-IV will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In certain embodiments, the kit comprises acontainer comprising a compound of Formula I-IV. In certain embodiments,the invention provides a kit for treating a hyperproliferative disorder.In another embodiment, the invention provides a kit for treating orpreventing a fungal or other eukaryote infection. The kit may furthercomprise a label or package insert on or associated with the container.In certain embodiments, the label or package inserts indicates that thecomposition comprising a compound of Formula I-IV can be used, forexample, to treat a hyperproliferative disorder or to treat a fungal orother eukaryote infection. The label or package insert may also indicatethat the composition can be used to treat other disorders.

In certain embodiments, the kit further comprises a container. Suitablecontainers include, for example, bottles, vials, syringes, blister pack,etc. The container may be formed from a variety of materials such asglass or plastic. The container holds a compound of Formula I-IV or apharmaceutical formulation thereof in an amount effective for treatingthe condition, and may have a sterile access port (for example, thecontainer may be an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle).

Alternatively, or additionally, the kit may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I-IV and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula I-IV and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

According to certain embodiments, the kit may comprise (a) a firstcontainer with a compound of Formula I-IV contained therein; andoptionally (b) a second container with a second pharmaceuticalformulation contained therein, wherein the second pharmaceuticalformulation comprises a second compound having, for example,anti-hyperproliferative or antifungal activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a pharmaceuticalformulation of a compound of Formula I-IV and a second formulationcomprising a second therapeutic agent, the kit may comprise a containerfor containing the separate formulations, such as a divided bottle or adivided foil packet; however, the separate compositions may also becontained within a single, undivided container. Typically, the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare administered in different dosage forms (e.g., oral and parenteral),are administered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I-IV, such as tablets or capsules.Such a kit includes, for example, a number of unit dosages. Such kitscan include a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

Although the compounds of Formula I-IV are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of KSPkinesin. Thus, they are also useful as pharmacological standards in thedevelopment of new biological tests and in the search for newpharmacological agents.

Representative compounds of the present invention, which are encompassedby the present invention include, but are not limited to the compoundsof the examples and their pharmaceutically acceptable salts, solvates,metabolites or prodrugs thereof. The examples presented below areintended to illustrate particular embodiments of the invention, and arenot intended to limit the scope of the specification or the claims inany way.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other KSP inhibitors of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF),dichloromethane (DCM), toluene, dioxane and 1,2-dichloroethane (DCE)were purchased from Aldrich in Sure seal bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters).

¹H-NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃, d₆-DMSO, CD₃OD orCDCl₃:CD₃OD solutions (reported in ppm), using trimethylsilane as thereference standard (0.00 ppm). When peak multiplicities are reported,the following abbreviations are used: s (singlet), d (doublet), t(triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, are reported inHertz (Hz).

Example 1

Synthesis of1-[2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

Step A: Preparation of (4-oxo-4-phenylbutyl)-carbamic acid tert-butylester: To a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (7.03 g, 38 mmol) in THF (130 mL) was added phenylmagnesiumbromide (1.0 M solution, 50 mL) at −78° C. After stirring for 2 hour at−78° C., HCl (2 M, 35 mL) was added to quench the reaction, which wasthen warmed to room temperature and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organics were washed with brine (50 mL)and dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford 9.56 g (96% yield) of the desired product.

Step B: Preparation of 2,5-difluorobenzoic acid hydrazide: To a solutionof 2,5-difluorobenzoic acid (3.5 g, 22 mmol) in THF/DMF (20 mL/20 mL)was added EDCI (4.7 g, 24 mmol), DMAP (50 mg) and NH₂NHBoc (3.07 g, 23.2mmol). After stirring for 16 hours, the reaction was quenched with water(30 mL) and diluted with EtOAc (30 mL). The organic layer was thenwashed with HCl (0.5 M, 20 mL), saturated NaHCO₃ (20 mL), and brine (20mL). The organic layer was then dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the crude Boc-protectedproduct, which was then dissolved in DCM (60 mL) at 0° C. TFA (50 mL)was added to the above DCM solution. After stirring for 2 hours, thereaction mixture was concentrated and the residue was dissolved in DCM(60 mL). The solution was washed with saturated NaHCO₃ (40 mL) and driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe desired crude product.

Step C: Preparation of{4-[(2,5-difluorobenzoyl)-hydrazono]-4-phenylbutyl}-carbamic acidtert-butyl ester: To a solution of (4-oxo-4-phenylbutyl)-carbamic acidtert-butyl ester (3.2 g, 12.2 mmol) and 2,5-difluorobenzoic acidhydrazide (2.1 g, 12 mmol) in EtOH (40 mL) was added HOAc (0.5 mL). Thereaction was then heated to reflux and stirred for 3 days. The reactionmixture was then cooled to room temperature and concentrated to givedesired product (5.1 g).

Step D: Preparation of{3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester: To a solution of{4-[(2,5-difluorobenzoyl)-hydrazono]-4-phenylbutyl}-carbamic acidtert-butyl ester (420 mg, 1.01 mmol) in DCE (2 mL) was added isobutyricanhydride (2 mL). The reaction mixture was then sealed and heat to 110°C. and stirred for 5 hours. The reaction was then cooled andconcentrated. The residue was purified by flash column chromatography(12:1 Hexanes/EtOAc) to provide the product (200 mg, 41%).

Step E: Preparation of1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one:To a solution of{3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (60 mg, 0.123 mmol) in DCM (2 mL) at 0° C. wasadded TFA (1 mL). After stirring for 10 minutes, the reaction wasconcentrated and the residue was purified by preparative thin layerchromatography (10:1:0.2 EtOAc/MeOH/30% NH₄OH) to provide the desiredproduct (25 mg, 53%). MS ESI (+) m/z 388 (M+1) detected; ¹H NMR (400MHz, CDCl₃) δ 7.59 (m, 2H), 7.50 (m, 1H), 7.39 (m, 3H), 7.18 (m, 2H),3.17 (m, 1H, J=7 Hz), 3.02 (m, 1H), 2.8 (br, 2H), 2.56 (m, 1H), 1.8 (br,2H), 1.6 (m, 2H), 1.2 (d, 3H, J=7 Hz), 1.13 (d, 3H, J=7 Hz).

The following compounds were synthesized in a similar manner using theappropriate hydrazide and anhydride.

Example 2

1-[2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-ethanone

MS ESI (+) m/z 360 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (m,2H), 7.50 (m, 1H), 7.37 (m, 3H), 7.18 (m, 2H), 3.05 (m, 1H), 2.9 (m,2H), 2.56 (m, 1H), 2.28 (s, 3H), 1.7 (m, 2H).

Example 3

1-[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

MS ESI (+) m/z 370 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d,1H, J=8 Hz), 7.56 (m, 1H), 7.52 (m, 2H), 7.42 (m, 1H), 7.35 (m, 3H), 7.2(m, 1H), 3.35 (m, 1H, J=7 Hz), 3.05 (m, 1H), 2.85 (t, 2H, J=7 Hz), 2.52(m, 1H), 1.62 (m, 2H), 1.17 (d, 3H, J=7 Hz), 1.11 (d, 3H, J=7 Hz).

Example 4

1-[2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

MS ESI (+) m/z 386 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.77 (d, 1H, J=8 Hz), 7.54 (m, 2H), 7.46 (d, 1H, J=8 Hz), 7.4-7.34(m, 4H), 3.37 (m, 1H, J=7 Hz), 3.05 (m, 1H), 2.81 (br, 2H), 2.52 (m,1H), 2.39 (br, 3H), 1.61 (m, 2H), 1.19 (d, 3H, J=7 Hz), 1.13 (d, 3H, J=7Hz).

Example 5

Synthesis of1-[2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one

Step A: Preparation of{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester: To a solution of (4-oxo-4-phenylbutyl)-carbamicacid tert-butyl ester (2.2 g, 8.5 mmol) in ethanol/DCM (30 mL/10 mL) wasadded 3-fluorothiobenzoic acid hydrazide (Takasugi, J. J.; Buckwalter,B. L. European patent EP 1004241, 2004) (1.2 g, 7.1 mmol) at roomtemperature. After stirring for 3 days, the reaction mixture wasconcentrated and purified by flash column chromatography (20:1Hexanes/EtOAc) to provide the product (2.65 g, 90%).

Step B: Preparation of{3-[5-(3-fluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester: To a solution of{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (400 mg, 0.96 mmol) in DCM (4 mL) was addedtriethylamine (130 mg, 1.3 mmol), followed by isobutyryl chloride (130mg, 1.3 mmol). After stirring for 1 hour, the reaction was quenched bythe addition of methanol (0.1 mL). The reaction mixture was concentratedand purified by flash column chromatography (15:1 Hexanes/EtOAc) toprovide the product (350 mg, 75%).

Step C: Preparation of1-[2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one:HCl (1 mL, 4 M in dioxane) was added to{3-[5-(3-fluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (100 mg, 0.21 mmol) at 0° C. After stirring for0.5 hours, the reaction was concentrated to give the desired product asthe dihydrochloride salt. MS ESI (+) m/z 386 (M+1) detected; ¹H NMR (400MHz, CDCl₃) δ 8.51 (s, 2H), 7.55 (m, 2H), 7.4-7.2 (m, 6H), 7.15 (m, 1H),3.43 (m, 2H), 3.06 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.8 (br, 1H), 1.2(d, 3H, J=7 Hz), 1.1 (d, 3H, J=7 Hz).

Example 6

2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylicacid dimethylamide

This compound was synthesized in a manner similar to that described inExample 5, substituting dimethylcarbamyl chloride for isobutyrylchloride. MS ESI (+) m/z 387 (M+1) detected; ¹H NMR (di-TFA salt, 400MHz, CDCl₃) δ 7.7 (s, 3H), 7.5-7.2 (m, 8H), 7.15 (m, 1H), 6.75 (br, 3H),3.2-2.9 (m, 3H), 3.02 (s, 6H), 2.38 (m, 1H), 2.1 (m, 1H), 1.8 (m, 1H).

Example 7

Synthesis of[2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-pyridin-2-yl-methanone

To a solution of{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (300 mg, 0.72 mmol) in DMF/THF (2 mL/2 mL) at roomtemperature were added picolinic acid (100 mg, 0.9 mmol), EDCI (170 mg,0.87 mmol), HOBT monohydrate (130 mg, 0.87 mmol), triethylamine (88 mg,0.87 mmol) and DMAP (2 mg). After stirring for 1 hour, EtOAc (20 mL) andsaturated NaHCO₃ (10 mL) were added to the reaction solution. The phaseswere separated and the aqueous layer was extracted with EtOAc (2×10 mL).The combined organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography (8:1 hexanes/EtOAc) to provide the Boc-protected product(130 mg, 35%). 51 mg of the product was cooled to 0° C., to which HCl (1mL, 4 M in dioxane) was added. After stirring for 0.5 hours, thereaction was concentrated to give the desired product as thetrihydrochloride salt. MS ESI (+) m/z 421 (M+1) detected; ¹H NMR (400MHz, CDCl₃) δ 9.05 (s, 1H), 8.6-8.2 (m, 5H), 7.85 (s, 1H), 7.7 (m, 2H),7.4-7.2 (m, 9 H), 7.1 (m, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 3.06 (m, 1H),2.5 (m, 1H), 2.1 (m, 2H).

Example 8

[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-pyridin-3-yl-methanone

The trihydrochloride salt of this compound was synthesized in a mannersimilar to that described in Example 7. MS ESI (+) m/z 421 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 9.6 (s, 1H), 8.81 (s, 2H), 8.43 (s,3H), 7.81 (br, 1H), 7.6 (m, 2H), 7.4-7.3 (m, 5H), 7.2 (m, 1H), 7.15 (m,1H), 3.58 (m, 1H), 3.2 (m, 1H), 3.0 (m, 1H), 2.4 (m, 1H), 2.15 (m, 2H).

Example 9

Synthesis of1-[5-(2,5-difluorophenyl)-2-(3-methylaminopropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

To a solution of{3-[5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-[1,3,4]oxadiazol-2-yl]-propyl}-methylcarbamicacid tert-butyl ester (13 mg, 0.027 mmol) in DMF (0.5 mL) was added toNaH (14 mg, 0.58 mmol, 60% dispersion in mineral oil) that waspreviously washed with hexanes. After stirring at room temperature for30 minutes, methyl iodide (23 mg, 0.16 mmol) was added. The reactionmixture was stirred at room temperature for 30 minutes and then dilutedwith saturated NaHCO₃ (20 mL). The mixture was extracted with ethylacetate (2×30 mL). The combined organics were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (8% to 20% ethylacetate in hexanes) to provide the Boc-protected product (6.6 mg, 48%).To this product in dichloromethane (1 mL) at 0° C. was added TFA (6 μL).After 30 minutes, more TFA (100 μL) was added and the mixture wasstirred for 1 hour. The reaction mixture was concentrated under a streamof N₂, diluted with dichloromethane (20 mL) and washed with 10% Na₂CO₃(20 mL). The mixture was extracted with dichloromethane (2×30 mL). Thecombined organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography (6:2:92 MeOH/triethylamine/ethyl acetate) to provide thefinal product (3.8 mg, 72%) as a yellow film. MS ESI (+) m/z 402 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.57 (m, 2H), 7.50 (m, 1H), 7.36 (m,3H), 7.16 (m, 2H), 3.37 (m, 1H), 3.03 (m, 1H), 2.68 (m, 2H), 2.54 (m,1H), 2.42 (s, 3H), 1.66 (m, 2H), 1.20 (d, 3H, J=6 Hz), 1.14 (d, 3H, J=7Hz).

Example 10

Synthesis of1-[5-(2,5-difluorophenyl)-2-(3-dimethylaminopropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

To a solution of1-[2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one(9 mg, 0.023 mmol) in MeOH (0.5 mL) was added paraforamidehyde (11 mg,0.35 mmol). The reaction mixture was heated to 70° C. and stirred for 2hours. After cooling to room temperature, a solution of sodiumcyanoborohydride (0.070 mL, 0.070 mmol, 1M in THF) was added. Themixture stirred for 20 minutes and then was diluted with half saturatedNaCl (50 mL) and extracted with ethyl acetate (3×25 mL). The combinedorganics were washed with saturated NaCl, dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography (2:40:60 triethylamine/ethylacetate/hexanes) to provide the product (5.1 mg, 53%). MS ESI (+) m/z416 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.57 (m, 2H), 7.50 (m,1H), 7.36 (m, 3H), 7.16 (m, 2H), 3.37 (m, 1H), 3.01 (m, 1H), 2.51 (m,1H), 2.34 (m, 2H), 2.20 (s, 6H), 1.66 (m, 2H), 1.20 (d, 3H, J=6 Hz),1.14 (d, 3H, J=7 Hz).

Example 11

Synthesis of1-[5-(2,5-difluorophenyl)-2-(3-isopropylaminopropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

To a solution of1-[2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one(12 mg, 0.031 mmol) in acetonitrile (0.5 mL) was added acetone (60 μL,0.082 mmol) and sodium triacetoxyborohydride (10 mg, 0.045 mmol). Afterstirring at room temperature for 45 minutes, more sodiumtriacetoxyborohydride (10 mg, 0.045 mmol) was added. The mixture stirredat room temperature for 5 hours. The reaction mixture was diluted with10% Na₂CO₃ (30 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organics were washed with brine (45 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography (40% to 100% ethyl acetate inhexanes with 2% triethylamine) to provide the final product (3.3 mg,25%). MS ESI (+) m/z 430 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.56(m, 2H), 7.50 (m, 1H), 7.36 (m, 3H), 7.15 (m, 2H), 3.36 (m, 1H), 3.01(m, 1H), 2.78 (m, 1H), 2.67 (m, 2H), 2.53 (m, 1H), 1.66 (m, 2H), 1.20(d, 3H, J=7 Hz), 1.14 (d, 3H, J=6 Hz), 1.04 (d, 6H, J=6 Hz).

Example 12

Synthesis of1-[5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one

Step A: Preparation of 4-hydroxy-1-phenylbutan-1-one: To a solution ofdihydrofuran-2-one (5.71 g, 66 mmol) in diethyl ether (70 mL) at −78° C.was slowly added phenyl lithium (24 mL, 40 mmol, 1.67 M solution incyclohexane/diethyl ether). After stirring at −78° C. for 2 hours, thereaction mixture was quenched by the addition of 10% NH₄Cl (35 mL). Themixture was warmed to room temperature and the layers separated. Theaqueous layer was extracted with diethyl ether (2×40 mL). The combinedorganics were washed with water (2×40 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography (2:3 hexanes/ethyl acetate) to provide theproduct (6.4 g, 97%) as pale yellow oil.

Step B: Preparation of4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one: To a solution of4-hydroxy-1-phenyl-butan-1-one (3.29 g, 20 mmol) in DMF (20 mL) wasadded tert-butylchlorodimethyl-silane (4.5 g, 30 mmol) and imidazole(4.1 g, 60 mmol). After stirring at room temperature for 14 hours, thereaction mixture was diluted with diethyl ether (150 mL) and washed with1M HCl (2×70 mL), water (2×70 mL) and brine (100 mL). The combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography (6%ethyl acetate in hexanes) to provide the product (5 g, 90%) as acolorless oil.

Step C: Preparation of 2,5-difluorobenzoic acid[4-(tert-butyldimethylsilanyloxy)-1-phenylbutylidene]-hydrazide: To asolution of 4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one (420mg, 1.5 mmol) in EtOH (4 mL) was added 2,5-difluorobenzoic acidhydrazide (260 mg, 1.5 mmol) and acetic acid (0.07 mL, 1.2 mmol). Afterstirring the reaction mixture at 90° C. for 5 hours, more acetic acid(0.1 mL) was added. The mixture was stirred at 90° C. for 40 hours andthen concentrated under reduced pressure. The mixture of startingmaterial and product was carried forward without further purification.

Step D: Preparation of1-[5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one:To a solution of crude 2,5-difluorobenzoic acid[4-(tert-butyl-dimethylsilanyloxy)-1-phenylbutylidene]-hydrazide fromthe previous step (200 mg) in dichloroethane (1 mL) was added isobutyricanhydride (73 mg, 0.46 mmol). After heating at 110° C. for 8 hours, themixture was concentrated under reduced pressure. The residue waschromatographed (7% ethyl acetate in hexanes) to provide thesilane-protected product (44 mg). To a solution of this product (28 mg,0.056 mmol) in acetonitrile (1 mL) was added 48% aq. HF (50 μL). Afterstirring at room temperature for 30 minutes, the mixture was dilutedwith saturated NaHCO₃ (30 mL) and extracted with ethyl acetate (3×20mL). The combined organics were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (30% ethyl acetate in hexanes) to provide theproduct (9 mg, 45%) as colorless film. MS ESI (+) m/z 389 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.57 (m, 2H), 7.51 (m, 1H), 7.39 (m,3H), 7.16 (m, 2H), 3.72 (m, 2H), 3.37 (m, 1H), 3.06 (m, 1H), 2.62 (m,1H), 1.77 (m, 1H), 1.67 (m, 1H), 1.21 (d, 3H, J=7 Hz), 1.15 (d, 3H, J=7Hz).

The following examples were prepared as previously described in Examples5 or 6 using the appropriate thiohydrazide, ketone and acid chloride orcarbamoyl chloride.

Example 13

[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-cyclopropylmethanone

MS APCI (+) m/z 384 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.40 (br,2H), 7.52 (m, 2H), 7.44 (m, 1H), 7.35 (m, 4H), 7.22 (m, 1H), 7.13 (m,1H), 3.32 (m, 1H), 3.04 (m, 1H), 2.98 (m, 1H), 2.74 (m, 1H), 2.42 (m,1H), 2.09 (m, 1H), 1.79 (m, 2H), 1.20 (m, 1H), 0.85 (m, 2H).

Example 14

1-[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methoxyethanone

MS APCI (+) m/z 387 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.37 (br,2H), 7.52 (m, 2H), 7.34 (m, 5H), 7.23 (m, 1H), 7.15 (m, 1H), 4.66 (d,1H, J=16 Hz), 4.44 (d, 1H, J=16 Hz), 3.56 (m, 1H), 3.37 (s, 3H), 3.15(m, 1H), 3.07 (m, 1H), 2.44 (m, 1H), 2.13 (m, 1H), 1.92 (m, 1H).

Example 15

1-(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxyethanone

MS APCI (+) m/z 404, 406 (M+1, Cl pattern) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.38 (br, 2H), 7.65 (s, 1H), 7.52 (d, 2H, J=8 Hz), 7.47 (d, 1H,J=8 Hz), 7.41 (d, 1H, J=8 Hz), 7.32 (m, 3H), 7.24 (m, 1H), 4.67 (d, 1H,J=16 Hz), 7.45 (d, 1H, J=16 Hz), 3.57 (m, 1H), 3.37 (s, 3H), 3.16 (m,1H), 3.07 (m, 1H), 2.44 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).

Example 16

(2-(3-Aminopropyl)-5-(3-chlorophenol)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopropyl)methanone

MS APCI (+) m/z 400, 402 (M+1, Cl pattern) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.40 (br, 2H), 7.71 (s, 1H), 7.50 (m, 3H), 7.40 (d, 1H), 7.34(m, 3H), 7.23 (m, 1H), 3.32 (m, 1H), 3.03 (m, 1H), 2.97 (m, 1H), 2.75(m, 1H), 2.43 (m, 1H), 2.09 (m, 1H), 1.79 (m, 1H), 1.20 (m, 1H), 0.86(m, 3H).

Example 17

1-(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one

MS APCI (+) m/z 402, 404 (M+1, Cl pattern) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.49 (br, 2H), 7.67 (s, 1H), 7.51 (m, 3H), 7.41 (d, 1H, J=8Hz), 7.33 (m, 3H), 7.23 (m, 1H), 3.44 (m, 2H), 3.07 (m, 2H), 2.43 (m,1H), 2.12 (m, 1H), 1.83 (m, 1H), 1.20 (d, 3H, J=6 Hz), 1.12 (d, 3H, J=7Hz).

Example 18

[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-morpholin-4-yl-methanone

MS APCI (+) m/z 429 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (br,2H), 7.56 (d, 2H), 7.34 (m, 5H), 7.24 (m, 1H), 7.11 (m, 1H), 3.71 (m,4H), 3.56 (m, 4H), 3.30 (m, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.41 (m,1H), 2.08 (m, 1H), 1.89 (m, 1H).

Example 19

Synthesis of1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)ethanone

MS ESI (+) m/z 358 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s,1H), 7.45 (s, 1H), 7.42 (d, 1H, J=9 Hz), 7.36 (m, 4H), 7.28 (d, 1H),7.14 (m, 1H), 3.20 (m, 1H), 2.87 (m, 1H), 2.53 (m, 1H), 2.44 (s, 3H),2.39 (m, 1H), 1.94 (m, 1H), 1.56 (m, 1H).

Example 20

(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclobutyl)methanone

MS ESI (+) m/z 398 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d,2H, J=7 Hz), 7.41 (d, 1H, J=11 Hz), 7.35 (m, 4H), 7.27 (m, 1H), 7.13 (m,1H), 3.87 (m, 1H), 3.22 (m, 1H), 2.95 (m, 1H), 2.88 (m, 1H), 2.39 (m,1H), 2.26 (m, 4H), 2.02 (m, 1H), 1.92 (m, 1H), 1.82 (m, 1H), 1.56 (m,1H).

Example 21

1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-ethylbutan-1-one

MS ESI (+) m/z 414 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d,2H, J=8 Hz), 7.40 (m, 3H), 7.33 (m, 2H), 7.25 (m, 1H), 7.14 (m, 1H),3.26 (m, 2H), 2.98 (m, 2H), 2.58 (br, 2H), 2.42 (m, 1H), 1.96 (m, 1H),1.71 (m, 1H), 1.63 (m, 1H), 1.51 (m, 3H), 0.95 (t, 3H, J=7 Hz), 0.83 (t,3H, J=7 Hz).

Example 22

1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one

MS ESI (+) m/z 372 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m,2H), 7.37 (m, 5H), 7.27 (m, 1H), 7.14 (m, 1H), 3.21 (m, 1H), 2.84 (m,4H), 2.58 (br, 2H), 2.39 (m, 1H), 1.92 (m, 1H), 1.55 (m, 1H), 1.15 (t,3H, J=7 Hz).

Example 23

1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)butan-1-one

MS ESI (+) m/z 386 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (m,3H), 7.38 (m, 2H), 7.33 (d, 2H), 7.27 (m, 1H), 7.13 (m, 1H), 3.21 (m,1H), 2.86 (br, 2H), 2.77 (m, 4H), 2.39 (m, 1H), 1.94 (m, 1H), 1.68 (m,1H), 1.55 (m, 2H), 0.97 (t, 3H, J=7 Hz).

Example 24

1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylbutan-1-one

MS ESI (+) m/z 400 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m,3H), 7.34 (m, 4H), 7.26 (m, 1H), 7.14 (m, 1H), 3.36 (m, 1H), 3.23 (m,1H), 2.86 (br, 2H), 2.39 (m, 3H), 1.93 (m, 1H), 1.75 (m, 1H), 1.54 (m,1H), 1.43 (m, 1H), 1.17 (dd, 3H, J=6.9 Hz, 12.3 Hz), 0.90 (dt, 3H, J=7.4Hz, 37.6 Hz).

Example 25

1-(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methylbutan-1-one

MS ESI (+) m/z 400 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (m,2H), 7.38 (m, 3H), 7.32 (m, 2H), 7.26 (m, 1H), 7.14 (m, 1H), 3.45 (br,2H), 3.23 (m, 1H), 2.87 (m, 2H), 2.74 (dd, 1H, J=7 Hz, 15 Hz), 2.63 (dd,1H, J=7 Hz, 15 Hz), 2.39 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.56 (m,1H), 0.95 (m, 6H).

Example 26

(2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopentyl)methanone

MS ESI (+) m/z 412 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (m,2H), 7.38 (m, 3H), 7.32 (m, 2H), 7.26 (m, 1H), 7.13 (m, 1H), 3.61 (m,1H), 3.22 (m, 1H), 2.85 (m, 2H), 2.40 (m, 3H), 1.95 (m, 3H), 1.82 (m,1H), 1.63 (m, 6H).

Example 27

1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)ethanone

MS ESI (+) m/z 376 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (m,1H), 7.40 (m, 4H), 7.30 (m, 1H), 7.13 (m, 2H), 3.20 (m, 1H), 2.89 (m,2H), 2.46 (s, 3H), 2.38 (m, 1H), 1.99 (m, 1H), 1.57 (m, 1H).

Example 28

1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one

MS ESI (+) m/z 404 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (m,1H), 7.42 (m, 2H), 7.34 (m, 2H), 7.26 (m, 1H), 7.10 (m, 2H), 3.48 (m,1H), 3.20 (m, 2H), 2.88 (m, 1H), 2.34 (m, 1H), 1.97 (m, 1H), 1.55 (m,1H), 1.18 (d, 3H, J=8 Hz), 1.16 (d, 3H, J=8 Hz).

Example 29

1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxyethanone

MS ESI (+) m/z 406 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (m,1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 7.12 (m, 2H), 4.55 (d,1H, J=16 Hz), 4.48 (d, 1H, J=16 Hz), 3.46 (s, 3H), 3.28 (m, 1H), 2.89(m, 2H), 2.40 (m, 1H), 1.96 (m, 1H), 1.58 (m, 1H).

Example 30

2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS ESI (+) m/z 405 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m,2H), 7.45 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.07 (m, 2H), 3.12 (m,1H), 3.01 (s, 6H), 2.85 (m, 1H), 2.36 (m, 1H), 1.95 (m, 1H), 1.65 (m,1H), 1.26 (m, 1H).

Example 31

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)ethanone

MS ESI (+) m/z 394 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.57 (m,1H), 7.32 (m, 1H), 7.23 (d, 1H, J=8 Hz), 7.11 (m, 3H), 6.97 (m, 1H),3.31 (m, 2H), 3.19 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.31 (m, 1H),1.95 (m, 1H), 1.58 (m, 1H).

Example 32

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one

MS ESI (+) m/z 422 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (m,1H), 7.32 (m, 1H), 7.23 (d, 1H, J=8 Hz), 7.11 (m, 3H), 6.96 (m, 1H),3.48 (m, 1H), 3.18 (m, 1H), 2.92 (m, 1H), 2.88 (m, 1H), 2.45 (br, 2H),2.31 (m, 1H), 1.93 (m, 1H), 1.52 (m, 1H), 1.20 (d, 3H, J=7 Hz), 1.18 (d,3H, J=7 Hz).

Example 33

1-(2-(4-aminobutan-2-yl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(diastereomer pair A)

Step A: Preparation of tert-butyl 3-methyl-4-oxo-4-phenylbutylcarbamate:To a solution of 3-methyl-2-pyrrolidinone (5.0 g, 50.4 mmol) inanhydrous THF (100 mL) at −78° C. was added n-butyllithium (2.1 Msolution, 25.2 mL, 53 mmol). The mixture was stirred for 30 min thentreated with a solution of Boc-anhydride (11.01 g, 50.4 mmol) inanhydrous THF (50 mL). After 3 hours at −78° C., phenyl magnesiumbromide (1.0 M solution, 65.6 mL, 65.6 mmol) was added via cannula.After a further 3 hours at −78° C. the mixture was treated with 2 N HCl(100 mL), warmed to room temperature and extracted with ethyl acetate(3×100 mL). The combined organic phases were washed with brine (100 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas chromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide theproduct (2.6 g, 18%) as a yellow oil.

Step B: Preparation of tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate:To a solution of 3-fluorobenzothiohydrazide (300 mg, 1.76 mmol) inethanol/DCM (6 mL/2 mL) was added tert-butyl3-methyl-4-oxo-4-phenylbutylcarbamate (538 mg, 1.94 mmol). Afterstirring at room temperature for 16 hours, acetic acid (3 drops) wasadded and the mixture stirred for another 48 hours. The reaction mixturewas then concentrated under reduced pressure and chromatographed (9:1hexanes/ethyl acetate) to provide the product (366 mg, 48%) as a mixtureof diastereomers as a yellow foam.

Step C: Preparation of tert-butyl3-(5-(3-fluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate:To a solution of tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate(50 mg, 116 mmol) in anhydrous DCM (5 mL) was added isobutyryl chloride(16 μL, 151 mmol) followed by triethylamine (21 μL, 151 mmol). Afterstirring at room temperature for 16 hours the mixture was partitionedbetween sat. NaHCO₃ (20 mL) and DCM (20 mL). The aqueous layer wasextracted with DCM (10 mL) and the combined organic phases were washedwith brine (20 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was chromatographed (19:1, hexanes/ethyl acetate)to afford two diastereomeric pairs, diastereomer pair A (more polar,13.1 mg) and diastereomer pair B (less polar, 11 mg).

Step D: Preparation of1-(2-(4-aminobutan-2-yl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(diastereomer pair A): To a solution of diastereomer pair A from theprevious step (13.1 mg, 0.026 mmol) in DCM (2 mL) was added TFA (0.5mL). After stirring at room temperature for 2 hours the mixture wasconcentrated under reduced pressure and partitioned between saturatedNaHCO₃ (20 mL) and ethyl acetate (20 mL). The aqueous layer wasextracted with ethyl acetate (10 mL) and the combined organic phaseswere washed with brine (10 mL), dried over Na₂SO₄ and concentrated underreduced pressure to provide the product as a diastereomer pair (10 mg,96%) as a pale yellow oil.

MS ESI (+) m/z 400 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.72 (m,2H), 7.48 (m, 2H), 7.41 (m, 1H), 7.34 (m, 2H), 7.25 (m, 1H), 7.16 (m,1H), 3.76 (m, 1H), 3.34 (m, 1H), 2.91 (br, 1H), 2.30 (br, 1H), 1.68 (m,1H), 1.37 (m, 1H), 1.13 (m, 6H), 0.98 (m, 3H), 0.88 (m, 1H).

Example 34

1-(2-(-4-aminobutan-2-yl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(diastereomer pair B)

Prepared as described in Example 33 using the less polar diastereomerpair B. MS ESI (+) m/z 400 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ7.71 (m, 2H), 7.48 (m, 2H), 7.41 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H),7.16 (m, 1H), 3.85 (m, 1H), 3.34 (m, 1H, J=6 Hz), 2.93 (br, 1H), 2.85(br, 1H), 2.52 (br, 1H), 1.66 (m, 1H), 1.26 (m, 1H), 1.12 (dd, 6H, J=6.8Hz, 14 Hz), 0.96 (d, 3H, J=7 Hz), 0.84 (m, 1H).

The following examples were prepared as previously described in Example7 using the appropriate thiohydrazide, ketone and carboxylic acid.

Example 35

(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-2-phenylethanone(diastereomer A)

Coupling with (R)-2-methoxy-2-phenylacetic acid provided diastereomericproducts that were isolated using silica gel chromatography (4:1hexanes/ethyl acetate). The more polar diastereomer (Boc-protecteddiastereomer A) was subjected to t-butoxycarbonyl group removal as inExample 7 to afford the product as the di-HCl salt. MS ESI (+) m/z 464(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.51 (br s, 3H), 7.4-7.0 (m,14H), 5.60 (s, 1H), 3.8-3.1 (m, 6H), 2.6-1.9 (m, 3H).

Example 36

(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-2-phenylethanone(diastereomer B)

Prepared as described in Example 35 using the less polar diastereomer(Boc-protected diastereomer B). MS ESI (+) m/z 464 (M+1) detected; ¹HNMR (400 MHz, CDCl₃) δ 8.30 (br s, 3H), 7.6-7.1 (m, 14H), 5.54 (s, 1H),3.4-2.3 (m, 8H), 1.7 (m, 1H).

Example 37

1-[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-(S)-methoxypropan-1-one

Obtained as a mixture of diastereomers. MS ESI (+) m/z 402 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.47 (br, 4H), 7.50 (m, 4H), 7.35(m, 10H), 7.22 (m, 2H), 7.15 (m, 2H), 4.66 (m, 2H), 3.54 (m, 2H), 3.38(s, 3H), 3.22 (s, 3H), 3.12 (m, 4H), 2.50 (m, 2H), 2.15 (m, 2H), 1.88(m, 1H), 1.78 (m, 1H), 1.54 (d, 3H, J=6 Hz), 1.37 (d, 3H, J=7 Hz).

Example 38

[2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-(tetrahydrofuran-3-yl)-methanone

Obtained as a mixture of diastereomers: MS ESI (+) m/z 414 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.19 (br, 3H), 7.52 (m, 2H), 7.35(m, 5H), 7.24 (m, 1H), 7.14 (m, 1H), 4.06-3.73 (m, 5H), 3.5-3.3 (m, 2H),3.2-2.9 (m, 2H), 2.45-2.05 (m, 4H).

Example 39

N—((S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methyl-1-oxobutan-2-yl)acetamide(diastereomer A)

Coupling with N-acetyl L-valine provided diastereomeric products thatwere isolated using silica gel chromatography (1:1 hexanes:ethylacetate). The more polar diastereomer (Boc-protected diastereomer A) wassubjected to t-butoxycarbonyl group removal as in Example 7 to affordthe product as the di-HCl salt. MS ESI (+) m/z 457 (M+1) detected; ¹HNMR (400 MHz, 10:1 CDCl₃:CD₃OD) δ 7.52-7.16 (m, 8H), 7.20 (m, 1H), 5.13(d, 1H, J=4 Hz), 3.31-2.92 (m, 2H), 2.98 (m, 1H), 2.40 (m, 1H), 2.07 (s,3H), 1.84 (m, 1H), 1.69 (m, 1H), 1.41 (m, 1H), 1.08 (d, 3H, J=6.3 Hz),0.87 (d, 3H, J=7.0 Hz).

Example 40

N—((S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methyl-1-oxobutan-2-yl)acetamide(diastereomer B)

Prepared as described in Example 39 using the less polar diastereomer(Boc-protected diastereomer B). MS ESI (+) m/z 457 (M+1) detected; ¹HNMR (400 MHz, CDCl₃) δ 8.33 (br s, 3H), 7.50-7.13 (m, 8H), 6.76 (m, 1H),5.43 (m, 1H), 3.31 (m, 1H), 3.19-2.81 (m, 2H), 2.57 (m, 1H), 2.36 (1H),2.16 (m, 1H), 1.81 (m, 4H), 1.04 (m, 3H), 0.93 (d, 3H, J=7.8 Hz).

Example 41

(2S)-1-(2-(3-Aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Obtained as a mixture of diastereomers. MS APCI (+) m/z 418, 420 (M+1,Cl pattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.46 (br, 4H), 7.65 (s,2H), 7.50 (m, 6H), 7.42 (d, 2H, J=8 Hz), 7.32 (m, 6H), 7.22 (m, 2H),4.66 (m, 2H), 3.52 (m, 2H), 3.38 (s, 3H), 3.22 (s, 3H), 3.12 (m, 4H),2.50 (m, 2H), 2.15 (m, 2H), 1.74 (m, 2H), 1.54 (d, 3H, J=7 Hz), 1.37 (d,3H, J=6 Hz).

Example 42

Synthesis of(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

To a solution of tert-butyl3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(50 mg, 0.11 mmol) and (S)-2-methoxypropanoic acid (22 μL, 0.23 mmol) inDMF (1 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (55 mg,0.29 mmol) and triethylamine (48 μL, 0.35 mmol). After stirring for 64hours, the reaction mixture was partitioned between ethyl acetate (20mL) and saturated NaHCO₃ (20 mL). The aqueous layer was extracted withethyl acetate (20 mL) and the combined organics were washed with water(5×10 mL) and brine (10 mL). The solution was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was chromatographed(9:1 to 4:1 hexanes/ethyl acetate) to provide the Boc-protected product(33 mg, 55%) as a pale yellow gum. To a solution of this product (33 mg,0.06 mmol) in dichloromethane (4 mL) at 0° C. was added TFA (1 mL).After stirring for 20 minutes, the mixture was concentrated underreduced pressure and partitioned between ethyl acetate (20 mL) andsaturated NaHCO₃ (20 mL). The aqueous layer was extracted with ethylacetate (20 mL). The combined organics were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toprovide the product as a mixture of diastereomers as a colorless gum (26mg, 97%). MS ESI (+) m/z 420 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ7.52 (m, 1H), 7.45 (m, 2H), 7.37 (m, 2H), 7.27 (m, 1H), 7.14 (m, 2H),4.71 (m, 1H), 3.35 (d, 3H, J=34 Hz), 3.28 (m, 1H), 2.91 (br, 2H), 2.72(br, 2H), 2.43 (m, 1H), 1.98 (m, 1H), 1.56 (m, 1H), 1.47 (dd, 3H, J=6.6Hz, 24.3 Hz).

The following examples were prepared as previously described in Example42 using the appropriate thiohydrazide, ketone and acid.

Example 43

(2S)-1-(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylbutan-1-one

Obtained as a mixture of diastereomers. MS ESI (+) m/z 418 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.45 (m, 2H), 7.34 (m,2H), 7.26 (m, 1H), 7.11 (m, 2H), 3.34 (m, 1H), 3.22 (m, 1H), 2.87 (br,2H), 2.73 (br, 2H), 2.38 (m, 1H), 1.96 (m, 1H), 1.74 (m, 1H), 1.54 (m,1H), 1.43 (m, 1H), 1.16 (m, 3H), 0.91 (dt, 3H, J=7.4 Hz, 35.2 Hz).

Example 44

(2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopropyl)methanone

MS ESI (+) m/z 402 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.60 (m,1H), 7.43 (m, 2H), 7.35 (m, 2H), 7.26 (m, 1H), 7.10 (m, 2H), 3.30 (br,1H), 3.16 (m, 1H), 2.87 (br, 1H), 2.75 (m, 1H), 2.35 (m, 1H), 1.97 (m,1H), 1.60 (m, 1H), 1.03 (m, 1H), 0.90 (m, 3H).

Example 45

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Obtained as a mixture of diastereomers. MS ESI (+) m/z 438 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.32 (m, 1H), 7.23 (d,1H, J=8 Hz), 7.14 (m, 3H), 6.98 (m, 1H), 4.68 (m, 1H), 3.37 (m, 1H),3.35 (d, 3H, J=34 Hz), 2.93 (m, 2H), 2.40 (m, 1H), 1.99 (m, 1H), 1.62(m, 1H), 1.48 (dd, 3H, J=6.6 Hz, 26 Hz), 1.36 (m, 1H), 1.25 (m, 1H).

Example 46

Synthesis of1-[2-(3-dimethylaminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one

To a solution of1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(9.0 mg, 0.02 mmol) in MeOH (1 mL) was added paraformaldehyde (10 mg,0.40 mmol). The mixture was heated to 70° C. for 2 hours. The mixturewas allowed to cool to room temperature and sodium cyanoborohydride(0.07 mL, 0.07 mmol, 1M solution in THF) was added. After stirring for40 minutes, the mixture was diluted with half saturated NaCl (50 mL) andextracted with ethyl acetate (3×25 mL). The combined organics werewashed with saturated NaCl, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography (2% triethylamine, 40% ethyl acetate in hexanes) toprovide the final product (3.0 mg, 30%) as pale yellow film. MS ESI (+)m/z 414 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m, 3H), 7.36 (m,5H), 7.14 (m, 1H), 3.51 (m, 1H), 3.17 (m, 1H), 2.40 (m, 3H), 2.23 (s,6H), 1.92 (m, 1H), 1.53 (m, 1H), 1.20 (d, 3H, J=7 Hz), 1.18 (d, 3H, J=7Hz).

Example 47

Synthesis of1-[5-(3-fluorophenyl)-2-(3-isopropylaminopropyl)-2-phenyl-[1,3,4]thiadiazol-3-yl]-2-methylpropan-1-one

A mixture of1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(9.0 mg, 0.02 mmol) and acetone (20 mg, 0.40 mmol) in acetonitrile (0.5mL) was stirred at room temperature for 1 hour. To the mixture was addedsodium triacetoxyborohydride (33 mg, 0.20 mmol). After stirring at roomtemperature for 16 hours, more acetone (50 μL) and sodiumtriacetoxyborohydride (14 mg) was added. The reaction mixture was heatedto 45° C. for 40 hours and then diluted with 10% Na₂CO₃ (30 mL). Themixture was extracted with ethyl acetate (3×30 mL). The combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography (2%triethylamine, 40% ethyl acetate in hexanes) to provide the product (5.4mg, 50%) as pale yellow film. MS ESI (+) m/z 428 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.45 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=7 Hz), 7.37 (m,4H), 7.27 (m, 1H), 7.14 (m, 1H), 3.50 (m, 1H), 3.21 (m, 1H), 2.80 (m,1H), 2.73 (m, 2H), 2.39 (m, 1H), 1.95 (m, 1H), 1.56 (m, 1H), 1.19 (d,3H, J=6 Hz), 1.17 (d, 3H, J=6 Hz), 1.05 (d, 6H, J=6 Hz).

Example 48

Synthesis of2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylicacid methyl-pyridin-2-yl-amide

To a solution of methyl-pyridin-2-yl-amine (77 mg, 0.71 mmol) andtriethylamine (150 mg, 0.15 mmol) in dichloroethane (3 mL) was addedtriphosgene (110 mg, 0.37 mmol). After stirring at room temperature for1 hour, the reaction mixture was concentrated under reduced pressure anddiluted with dichloroethane (3 mL). To the solution was added{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (250 mg, 0.60 mmol) and DMAP (20 mg). Afterstirring at room temperature for 3 hours, the reaction mixture wasconcentrated under reduced pressure and purified by flash columnchromatography (1:8 ethyl acetate/hexanes) to provide the Boc-protectedproduct (210 mg, 54%). To this product (65 mg, 0.12 mmol) was added HCl(3 mL, 4M in dioxane) at 0° C. After warming to room temperature andstirring for 3 minutes, the mixture was concentrated to provide thefinal product as the trihydrochloride salt (64 mg, 97%). MS APCI (+) m/z450 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.62 (m, 3H), 7.60 (d, 2H,J=6 Hz), 7.35 (m, 5H), 7.19 (d, 1H, J=7 Hz), 7.13 (m, 1H), 7.06 (d, 1H,J=8 Hz), 3.67 (s, 3H), 3.50 (m, 1H), 3.25 (m, 1H), 3.13 (m, 1H), 2.50(m, 1H), 2.23 (m, 2H).

Example 49

2-(3-Aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylicacid pyridin-3-ylamide

Prepared as previously described in Example 48 using pyridin-3-amine inplace of methylpyridin-2-yl-amine. MS APCI (+) m/z 436 (M+1) detected;¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.75 (d, 1H), 8.29 (m, 1H), 7.78(m, 1H), 7.73 (m, 1H), 7.52 (m, 3H), 7.40 (m, 3H), 7.35 (m, 2H), 7.18(m, 1H), 3.39 (m, 2H), 3.23 (m, 1H), 3.13 (m, 1H), 3.06 (m, 1H), 2.58(m, 1H), 2.25 (br, 1H), 2.00 (br, 1H).

Example 50

Synthesis of(2S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one(diastereomer A)

(S)-2-hydroxy-3-methylbutyric acid (13.5 mg, 0.11 mmol) and PyBOP (60mg, 0.12 mmol) were combined in THF (0.4 mL) and stirred for 10 minutes.To this mixture was added{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (20 mg, 0.05 mmol) and DIEA (31 mg, 0.24 mmol).After stirring at room temperature for 24 hours, the reaction mixturewas diluted with 10% Na₂CO₃ (20 mL) and extracted with ethyl acetate(3×20 mL). The combined organics were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed(1:4 ethyl acetate/hexanes) to provide Boc-protected diastereomer A(less polar, 2.0 mg) and Boc-protected diastereomer B (more polar, 4.2mg). To the Boc-protected diastereomer A was added HCl (1 mL, 4M indioxane) at 0° C. After warming to room temperature and stirring for 1hour, the mixture was concentrated under a stream of N₂. The residue wasdissolved in an ether/dioxane mixture and precipitated with hexanes. Thesolid was filtered and washed with hexanes to provide the final productas yellow solid. MS ESI (+) m/z 416 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.4 (br s, 3H), 7.5 (m, 2H), 7.43-7.28 (m, 4H), 7.24-7.11 (m,3H), 4.66 (br s, 1H), 3.30 (br s, 1H), 3.15-2.92 (m, 2H), 2.73 (m, 1H),2.30 (m, 1H), 2.18 (m, 1H), 1.81-1.49 (m, 2H), 1.10 (br m, 3H), 0.9 (brm, 3H).

Example 51

(2S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one(diastereomer B)

Prepared as previously described in Example 50 using the more polarBoc-protected diastereomer B. MS ESI (+) m/z 416 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 8.3 (br s, 3H), 7.65 (m, 2H), 7.45-7.30 (m, 5H),7.28-7.12 (m, 2H), 4.89 (br s, 1H), 3.86 (br m, 1H), 3.13 (br m, 1H),3.05-2.82 (m, 2H), 2.27-2.14 (m, 2H), 2.05 (br m, 1H), 1.91 (br m, 1H),1.02 (d, 3H, J=7.0 Hz), 0.60 (d, 3H, J=6.3 Hz).

Example 52

2-amino-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one

Step A: Preparation of tert-butyl1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-ylcarbamate:2-(3-Azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(50 mg, 0.139 mmol; as prepared in example 70) was dissolved in 2.0 mLof DMF. 2-(tert-Butoxycarbonyl)propanoic acid (39 mg, 0.208 mmol), EDCI(40 mg, 0.208 mmol), HOBt (28 mg, 0.208 mmol) and TEA (0.058 mL, 0.417mmol) were then added and the reaction allowed to stir at 23° C.Following 12 hours, the reaction was quenched by addition of saturatedNaHCO₃ solution, extracted (3×15 mL ethyl acetate), combined organicswashed with water (1×50 mL) then dried over Na₂SO₄, and concentrated invacuo. The crude reaction was purified by chromatography (20% ethylacetate/Hex) affording the product as a white foam (70 mg, 94%). MS APCI(−) m/z 529 (M−1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H), 7.43(m, 2H), 7.37 (t, 2H, J=8 Hz), 7.30 (m, 1H), 7.12 (m, 2H), 5.23 (brs,0.5H), 5.12 (brs, 0.5H), 3.44 (m, 2H), 3.19 (m, 1H), 2.47 (m, 1H), 1.57(d, 2H, J=9 Hz), 1.43 (m, 12H), 0.89 (m, 1H).

Step B: Preparation of2-amino-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one:tert-Butyl1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-ylcarbamate(70 mg, 0.131 mmol) was dissolved in 7.0 mL of EtOH. HCl (0.65 mL, 0.659mmol) was then added and the reaction stirred at 23° C. for 4 hours. Thereaction was then concentrated and purified by chromatography (2-10%MeOH/DCM), yielding the product (54 mg, 95%) as a yellow oil. MS ESI (+)m/z 431 (M+1) detected; ¹H NMR (400 MHz, CD₃OD) δ7.69 (m, 1H), 7.53 (d,2H, J=8 Hz), 7.42 (t, 2H, J=7 Hz), 7.34 (m, 3H), 4.91 (m, 3H), 3.21 (m,1H), 3.17 (m, 2H), 2.68 (m, 1H), 2.19 (m, 1H), 1.99 (m, 1H), 1.73 (d,1.5H, J=8 Hz), 1.64 (d, 1.5H, J=8 Hz).

Step C: Preparation of 2-amino-1-(2-(3-aminopropyl)-5-(2,5difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one:2-Amino-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one(50 mg, 0.116 mmol) was dissolved in 5.0 mL of MeOH. HCl (0.46 ml, 0.464mmol) was added followed by evacuation/re-vacuation with N₂. Pd/C (12mg, 0.011 mmol) was then added followed by H₂ balloon. Following 40hours at 23° C., the reaction was concentrated in vacuo, affording theproduct (41 mg, 87%) as a cream/yellow colored foam. MS ESI (+) m/z 405(M+1) detected; ¹H NMR (400 MHz, CD₃OD) δ7.68 (m, 1H), 7.53 (m, 2H),7.42 (t, 2H, J=9 Hz), 7.34 (m, 3H), 4.92 (m, 1H), 3.22 (m, 2H), 3.17 (m,4H), 2.65 (m, 2H), 2.20 (m, 1H), 1.99 (m, 1H), 1.72 (d, 1.5H, J=8 Hz),1.66 d, 1.5H, J=8 Hz).

Example 53

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one

Prepared as previously described in Example 52 using the appropriatethiohydrazide, ketone and carboxylic acid to provide the Boc-protectedproduct. To this product (0.087 g, 0.167 mmol) dissolved in ether (5 mL)was added HCl (0.654 mL, 1.67 mmol, solution in ether). After stirringat room temperature for 1 hour, the mixture was concentrated underreduced pressure to provide the final product as a mixture ofdiastereomers. MS ESI (+) m/z 422 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 7.43 (m, 2H), 7.36 (m, 3H), 7.33 (m, 1H), 7.15 (m, 2H), 5.03(s, 1H), 4.83 (m, 1H), 3.19 (m, 1H), 2.93 (m, 2H), 2.42 (m, 1H), 1.57(m, 4H), 1.49 (d, 3H).

Example 54

Synthesis of2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylicacid 2-methoxyethyl ester

To a solution of 2-methoxyethanol (30 mg, 0.4 mmol) in acetonitrile (3mL) at 0° C. was added phosgene (54 mg, 0.54 mmol, 20% wt in toluene).After warming to room temperature and stirring for 6 hours, the mixturewas concentrated under reduced pressure. To the residue was addeddichloromethane (4 mL),{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (90 mg, 0.22 mmol), triethylamine (33 mg, 0.32mmol) and DMAP (10 mg). After stirring for 1 hour, MeOH (0.5 mL) wasadded to quench the reaction. The mixture was concentrated under reducedpressure and purified by flash column chromatography (8:1 hexanes/ethylacetate) to provide the Boc-protected product (90 mg, 80%). To 41 mg ofthis product was added HCl (3 mL, 4M in dioxane) at 0° C. After warmingto room temperature and stirring for 1 hour, the mixture wasconcentrated to provide the final product as the dihydrochloride salt(39 mg, 100%). MS APCI (+) m/z 418 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.45 (br, 2H), 7.55 (m, 2H), 7.36 (m, 5H), 7.25 (m, 1H), 7.10(m, 1H), 4.25 (m, 1H), 3.58 (m, 1H), 3.33 (s, 3H), 3.22 (m, 1H), 3.10(m, 2H), 2.53 (m, 1H), 2.18 (m, 1H), 1.91 (m, 1H), 1.77 (s, 2H).

Example 55

Synthesis of2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-[1,3,4]thiadiazole-3-carboxylicacid ethylamide

To a solution of{3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamicacid tert-butyl ester (40 mg, 0.096 mmol) in dichloroethane (3 mL) wasadded ethyl isocyanate (140 mg, 1.9 mmol). After stirring at 60° C. for1 hour, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (8:1 hexanes/ethyl acetate) to provide theBoc-protected product (40 mg, 85%). To this product was added HCl (3 mL,4M in dioxane) at 0° C. After warming to room temperature and stirringfor 1 hour, the mixture was concentrated to provide the final product asthe dihydrochloride salt (37 mg, 98%). MS APCI (+) m/z 387 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (br, 2H), 7.49 (m, 2H), 7.34(m, 5H), 7.24 (m, 1H), 7.10 (m, 1H), 6.19 (m, 1H), 3.26 (m, 3H), 3.04(m, 1H), 2.99 (m, 1H), 2.44 (m, 1H), 2.11 (m, 1H), 1.92 (m, 1H), 1.15(t, 3H).

Example 56

Synthesis of2-(3-aminopropyl)-5-(3-fluorophenyl)-N-(2-methoxyethyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

Step A: Preparation of 4-nitrophenyl2-(3-(tert-butoxycarbonyl)propyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate:To a solution of tert-butyl345-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(350 mg, 0.84 mmol) in dichloromethane (3 mL) was added triethylamine(110 mg, 1.10 mmol) and 4-nitrophenylchloroformate (220 mg, 1.00 mmol).After stirring for 1 hour, the reaction mixture was diluted with 1M HCl(5 mL) and dichloromethane (10 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure to provide theproduct.

Step B: Preparation of2-(3-aminopropyl)-5-(3-fluorophenyl)-N-(2-methoxyethyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide:To a solution of 4-nitrophenyl2-(3-(tert-butoxycarbonyl)propyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate(90 mg, 0.20 mmol) in dichloroethane (3 mL) was added2-methoxy-N-methylethanamine (70 mg, 0.80 mmol) and DIEA (100 mg, 0.80mmol). After stirring at 50° C. for 6 hours, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residuewas purified by flash column chromatography (1:10 ethyl acetate/hexanes)to provide the Boc-protected product (60 mg, 70%). To this product wasadded HCl (3 mL, 4M in dioxane) at 0° C. After warming to roomtemperature and stirring for 1 hour, the mixture was concentrated toprovide the final product as the dihydrochloride salt (50 mg, 83%). MSAPCI (+) m/z 431 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.41 (br,2H), 7.55 (m, 2H), 7.32 (m, 6H), 7.09 (m, 1H), 3.63 (m, 3H), 3.35 (s,3H), 3.01 (s, 3H), 2.41 (m, 1H), 2.05 (m, 1H), 1.80 (m, 2H), 1.26 (m,2H) 0.88 (m, 1H).

The following examples were prepared as previously described in Example56 using the appropriate amine.

Example 57

2-(3-Aminopropyl)-N-cyclopropyl-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS APCI (+) m/z 399 (M+1) detected.

Example 58

2-(3-Aminopropyl)-5-(3-fluorophenyl)-N-(2-methoxyethyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS APCI (+) m/z 417 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (br,2H), 7.47 (m, 2H), 7.32 (m, 5H), 7.23 (m, 1H), 7.10 (m, 1H), 6.58 (m,1H), 3.42 (m, 3H), 3.35 (s, 3H), 3.25 (m, 1H), 3.01 (m, 2H), 2.46 (m,2H), 2.10 (m, 1H), 1.88 (m, 1H).

Example 59

2-(3-Aminopropyl)-N-ethyl-5-(3-fluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS APCI (+) m/z 401 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.36 (br,2H), 7.52 (m, 2H), 7.32 (m, 5H), 7.21 (m, 1H), 7.09 (m, 1H), 3.39 (m,2H), 3.25 (m, 1H), 2.97 (m, 1H), 2.92 (s, 3H), 2.39 (m, 1H), 2.16 (m,1H), 2.06 (m, 1H), 1.84 (m, 1H), 1.22 (m, 3H).

Example 60

2-(3-Aminopropyl)-N,N-diethyl-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS APCI (+) m/z 415 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.42 (br,2H), 7.52 (m, 2H), 7.33 (m, 5H), 7.21 (m, 1H), 7.08 (m, 1H), 3.35 (m,4H), 3.24 (m, 1H), 2.96 (m, 2H), 2.46 (m, 1H), 2.07 (m, 1H), 1.85 (m,1H), 1.20 (m, 6H).

Example 61

2-(3-Aminopropyl)-5-(3-chlorophenyl)-N,N-dimethyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS APCI (+) m/z 403, 405 (M+1, Cl pattern) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.44 (br, 2H), 7.62 (s, 1H), 7.54 (d, 2H), 7.45 (d, 1H), 7.36(d, 1H), 7.32 (m, 3H), 7.23 (m, 1H), 3.29 (m, 1H), 3.00 (s, 6H), 2.91(m, 1H), 2.38 (m, 1H), 2.07 (m, 1H), 1.87 (m, 1H), 1.72 (m, 1H).

Example 62

Synthesis of(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one(diastereomer A)

Step A: Preparation of tert-butyl3-(3-((R)-2-((2,2-dimethyl-1,1-diphenylpropyl)dimethylsilyloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate:To a solution of(R)-2-((2,2-dimethyl-1,1-diphenylpropyl)dimethylsilyloxy)propanoic acid(181 mg, 0.36 mmol) and DIEA (78 mg, 0.60 mmol) in acetonitrile (1 mL)was added HATU (137 mg, 0.36 mmol). After stirring at room temperaturefor 10 minutes, a solution of tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(100 mg, 0.24 mmol) in acetonitrile (1 mL) was added. After stirring for3 hours, PyBOP (150 mg), DIEA (100 μL), and more tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(45 mg) was added. After stirring for 16 hours, the reaction mixture wasdiluted with 10% Na₂CO₃ (30 mL) and extracted with ethyl acetate (3×20mL). The combined organics were washed with brine (40 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas chromatographed (1:9 ethyl acetate/hexanes) to provide theN-Boc-O-TBDPS-protected diastereomer A (more polar, 74 mg, 40%) and theN-Boc-O-TBDPS-protected diastereomer B (less polar, 35 mg, 19%)

Step B: Preparation of(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one(diastereomer A): To a solution of the N-Boc-O-TBDPS-protecteddiastereomer A (36 mg, 0.047 mmol) in THF (0.5 mL) was added TBAF (94 μLof 1.0 M solution in THF). After stirring for 3 hours at roomtemperature, the mixture was diluted with half saturated NaHCO₃ (30 mL)and extracted with ethyl acetate (3×20 mL). The combined organics werewashed with brine (30 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was chromatographed (30% ethylacetate in hexanes) to provide the N-Boc-protected diastereomer A (18mg, 80%). To a cooled (0° C.) solution of this product in dioxane (0.5mL) was added HCl (0.5 mL of 4.0 M solution in dioxane). After warmingto room temperature, the mixture was stirred for 4.5 hours. The reactionmixture was concentrated under reduced pressure and dissolved in minimaldioxane and then precipitated with ether to provide the final product(3.9 mg, 70%). MS ESI (+) m/z 388 (M+1) detected; ¹H NMR (400 MHz, 10:1CDCl₃:CD₃OD) δ 7.40 (m, 8H), 7.19 (m, 1H), 4.98 (m, 1H), 3.32 (m, 1H),3.05 (m, 2H), 2.56 (m, 1H), 2.18 (m, 1H), 1.70 (m, 1H), 1.57 (m, 3H).

Example 63

(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one(diastereomer B)

Prepared as previously described in Example 62 using theN-Boc-O-TBDPS-protected diastereomer B from Step A of Example 62. MS ESI(+) m/z 388 (M+1) detected; ¹H NMR (400 MHz, 10:1 CDCl₃:CD₃OD) δ7.53-7.30 (m, 8H), 7.19 (m, 1H), 5.10 (m, 1H), 3.53 (m, 1H), 3.24-2.95(m, 2H), 2.55 (m, 1H), 2.19 (m, 1H), 1.87 (m, 1H), 1.49 (m, 3H).

Example 64

Synthesis of(S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Step A: Preparation of tert-butyl3-((S)-3-((S)-2-(tert-butyldiphenylsilyloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate:To a solution of tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(0.54 g, 1.30 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid(0.64 g, 1.95 mmol) in DMF (10 mL) was added PyBOP (1.01 g, 1.95 mmol)followed by DIEA (0.34 g, 2.60 mmol). After stirring at room temperaturefor 14 hours, the reaction mixture was partitioned between 10% Na₂CO₃(100 mL) and ethyl acetate (100 mL). The aqueous layer was extractedwith ethyl acetate (40 mL). The combined organics were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed (1:9 to 1:4 ethylacetate/hexanes) to provide the less polar diastereomer product (180 mg,19%) as a yellow syrup.

Step B: Preparation of tert-butyl3-((S)-5-(3-fluorophenyl)-3-((S)-2-hydroxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate:To a cooled (0° C.) solution of tert-butyl3-(3-((S)-2-(tert-butyldiphenylsilyloxy)propanoyl)-5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(180 mg, 0.25 mmol) in THF (2.5 mL) was added TBAF (0.40 mL of 1Msolution in THF). After stirring at room temperature for 2 hours, thevolume was reduced in vacuo and the mixture was diluted withhalf-saturated NaHCO₃ (30 mL). The mixture was extracted with ethylacetate (3×20 mL) and the combined organics were washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed (30% ethyl acetate in hexanes)to provide the product (95 mg, 79%) as a viscous, yellow syrup.

Step C: Preparation of(S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one:To a solution of tert-butyl3-((S)-5-(3-fluorophenyl)-3-((S)-2-hydroxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(64 mg, 0.13 mmol) in acetonitrile (1.3 mL) was added Ag₂O (150 mg, 0.66mmol) followed by iodomethane (190 mg, 1.3 mmol). After stirring at roomtemperature for 9 hours, the mixture was filtered, concentrated underreduced pressure and chromatographed (20% ethyl acetate in hexanes) toprovide the Boc-protected product (30 mg, 45%). To this product wasadded HCl (0.5 mL of 4 M solution in dioxane). After stirring at 0° C.for 10 minutes and then at room temperature for 90 minutes, the mixturewas concentrated under reduced pressure to provide the product (26 mg,95%) as the di-HCl salt. MS ESI (+) m/z 402 (M+1) detected; ¹H NMR (400MHz, 10:1 CDCl₃:CD₃OD) δ 7.38 (m, 6H), 7.30 (m, 2H), 7.19 (m, 1H), 4.86(br q, 1H, J=6.3 Hz), 3.43 (s, 3H), 3.36 (m, 1H), 3.12 (m, 2H), 2.56 (m,1H), 2.21 (m, 2H), 1.44 (m, 3H).

Absolute stereochemistry was assigned by examination of theprotein:inhibitor co-crystal structure of Eg5 and(S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 65

(2R)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Prepared as in Example 42 using appropriately substituted reagents. MS(+) m/z 402 (M+1) detected; ¹H NMR (400 MHz, 10:1 CDCl₃:CD₃OD) δ7.49-7.29 (m, 8H), 7.20 (m, 1H), 4.77 (br 1, 1H, J=6.3 Hz), 3.35-3.26(m, 4H), 3.10 (m, 2H), 2.61 (m, 1H), 2.22 (m, 1H), 1.68 (m, 1H), 1.52(m, 3H).

Example 66

(S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-ethoxypropan-1-one

Prepared as described in Example 64 using ethyl iodide in place ofmethyl iodide. MS (+) m/z 416 (M+1) detected; ¹H NMR (400 MHz, 10:1CDCl₃:CD₃OD) δ 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H,J=6.3 Hz), 3.68-3.53 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.58 (m, 1H),2.21 (m, 1H), 1.72 (m, 1H), 1.47 (d, 3H, J=6.3 Hz), 1.24 (m, 3H).Stereochemistry was assigned by inference from(S)-1-(S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 67

Synthesis of2-(3-aminopropyl)-5-(3-fluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

Step A: Preparation of tert-butyl3-(5-(3-fluorophenyl)-3-(1-carbonyl-3-methylimidazoliumiodide)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate: To asolution of tert-butyl3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(500 mg, 1.20 mmol) in THF (8 mL) was added 1,1′-carbonyl diimidazole(234 mg, 1.44 mmol). After heating to 70° C. in a sealed vessel for 2hours, the mixture was cooled to room temperature and concentrated underreduced pressure. The residue was dissolved in dichloromethane (20 mL)and washed with 0.5 M HCl (2×10 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure to provide thecrude imidazole intermediate. To this product was added acetonitrile (3mL) followed by methyl iodide (854 mg, 6.02 mmol). After stirring atroom temperature for 24 hours, the mixture was concentrated underreduced pressure to provide the crude product (778 mg, 99%).

Step B: Preparation of2-(3-aminopropyl)-5-(3-fluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide:To a solution of tert-butyl3-(5-(3-fluorophenyl)-3-(1-carbonyl-3-methylimidazoliumiodide)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (157mg, 0.241 mmol) and triethylamine (122 mg, 1.21 mmol) in THF (3 mL) wasadded N-methoxymethanamine hydrochloride (47 mg, 0.48 mmol). Afterstirring at room temperature for 2 hours, the mixture was concentratedunder reduced pressure and chromatographed (10:1 hexanes/ethyl acetate)to provide the Boc-protected product (87 mg, 72%). To this product wasadded HCl (2 mL of 4M in dioxane). After stirring at room temperaturefor 30 minutes, the mixture was concentrated under reduced pressure toprovide the final product as the dihydrochloride salt. MS APCI (+) m/z403 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (br, 2H), 7.54 (br,2H), 7.36 (m, 5H), 7.22 (m, 1H), 7.11 (m, 1H), 3.74 (s, 3H), 3.34 (br,1H), 3.16 (s, 3H), 3.06 (br, 2H), 2.50 (br, 1H), 2.12 (br, 1H), 1.91(br, 1H).

The following examples were prepared as previously described in Example67 using the appropriate thiohydrazide, ketone, and alkoxyamine oralcohol.

Example 68

2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

MS ESI (+) m/z 421 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.79 (br,3H), 7.47 (m, 1H), 7.40 (d, 2H), 7.34 (m, 2H), 7.28 (d, 1H), 7.11 (m,2H), 3.68 (s, 3H), 3.17 (s, 3H), 3.13 (m, 1H), 3.06 (m, 1H), 2.97 (m,1H), 2.31 (m, 1H), 2.11 (m, 1H), 1.74 (m, 1H).

Example 69

Methyl2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate

MS APCI (+) m/z 374 (M+1) detected.

Example 70

Ethyl2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate

MS APCI (+) m/z 388 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (br,2H), 7.55 (br, 2H), 7.35 (m, 5H), 7.24 (m, 1H), 7.10 (m, 1H), 4.22 (br,1H), 4.11 (br, 1H), 3.26 (br, 1H), 3.08 (br, 2H), 2.50 (br, 1H), 2.17(br, 1H), 1.91 (br, 1H), 1.26 (br, 3H).

Example 71

Synthesis of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Step A: Preparation of 4-azido-1-phenylbutan-1-one: To a solution of4-chloro-1-phenylbutan-1-one (26.4 mL, 164 mmol) in DMSO (200 mL) wasadded sodium azide (12.8 g, 197 mmol). The solution was warmed to 55° C.and stirred for 16 hours. The cooled mixture was then treated with water(600 mL) and extracted with ether (3×200 mL). The combined organics werewashed with water (8×100 mL) and brine (100 mL) then dried over MgSO₄and concentrated to provide the product as an orange oil (30.7 g, 99%).

Step B: Preparation of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole:To a solution of 2,5-difluorobenzothiohydrazide (1.5 g, 7.97 mmol) inEtOH/dichloromethane (3:1, 16 mL) was added 4-azido-1-phenylbutan-1-one(1.36 g, 7.17 mmol). After stirring at room temperature for 16 hours,acetic acid (2 drops) was added and the mixture was stirred for another16 hours. The reaction mixture was then concentrated under reducedpressure and chromatographed (9:1 hexanes/ethyl acetate) to provide theproduct (1.41 g, 41%) as a bright yellow syrup.

Step C: Preparation of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-oneand(S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one:To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg,1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol)followed by DIEA (0.378 mL, 2.17 mmol). After stirring at roomtemperature for 15 minutes, a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring atroom temperature for 16 hours, the mixture was concentrated underreduced pressure and partitioned between saturated NaHCO₃ (50 mL) andethyl acetate (50 mL). The aqueous layer was extracted with ethylacetate (2×30 mL) and the combined organic phases were washed with brine(20 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate)to provide the less polar diastereomer,(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one(121 mg) and the more polar diastereomer,(S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one(175 mg) as pale yellow oils. Absolute stereochemistry was assigned byexamination of a protein:inhibitor co-crystal structure of Eg5 and(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Step D: Preparation of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one:To a solution of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one(121 mg, 0.18 mmol) in THF (5 mL) at 0° C. was added TBAF (0.31 mL, 1M,0.31 mmol). After stirring at 0° C. for 1 hour and at room temperaturefor 1 hour, the mixture was treated with saturated NaHCO₃ (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organics werewashed with brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated. The brown oil was chromatographed (4:1 hexanes/ethylacetate) to provide the product (41 mg, 53%) as a pale yellow oil.

Step E: Preparation of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one:To a solution of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one(41 mg, 0.095 mmol) in DMF (2 mL) at 0° C. was added methyl iodide (50μL, 0.48 mmol) followed by sodium hydride (10 mg, 60%). After stirringat 0° C. for 30 minutes and room temperature for 3 hours, the mixturewas treated with saturated NH₄Cl (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic phases were washed with water(6×10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide the product (40 mg, 94%)as a yellow oil.

Step F: Preparation of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one:To a suspension of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one(102 mg, 0.23 mmol) in MeOH (2.2 mL) was added conc. HCl (57 μL, 0.69mmol) followed by 10% Pd/C (10 mg, wet, Degussa type). After stirringunder a H₂ balloon for 1 hour, the mixture was filtered and concentratedunder reduced pressure. The colorless glass was triturated with diethylether and filtered to provide the di-HCl salt product as a white solid(89 mg, 79%). MS ESI (+) m/z 420 (M+1) detected; ¹H NMR (400 MHz, CDCl₃)δ 7.52 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 7.13 (m, 2H),4.70 (m, 1H), 3.40 (s, 3H), 3.27 (m, 1H), 2.88 (m, 2H), 2.43 (m, 1H),1.96 (m, 1H), 1.57 (m, 1H), 1.45 (d, 3H, J=7 Hz). Absolutestereochemistry assigned by examination of a protein:inhibitorco-crystal structure of Eg5 and(S)-1-(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 72

(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Prepared as previously described in Example 71 using(S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(tert-butyldiphenylsilyloxy)propan-1-onefrom Step C. MS ESI (+) m/z 420 (M+1) detected; ¹H NMR (400 MHz, CDCl₃)δ 7.51 (m, 1H), 7.44 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H),4.71 (q, 1H, J=6 Hz), 3.32 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.43 (m,1H), 1.93 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.44 (m, 2H), 1.34 (m, 1H).Stereochemistry was assigned by inference from(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 73

Synthesis of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one

To a solution of(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-oneprepared as described in Example 71 (74 mg, 0.172 mmol) in MeOH (5 mL)was added 1N HCl/MeOH (0.5 mL) followed by 10% Pd/C (10 mg, wet, Degussatype). After stirring under a H₂ balloon for 1 hour, the mixture wasfiltered and concentrated under reduced pressure. The colorless glasswas triturated with diethyl ether and filtered to provide the di-HClsalt product as a white solid (54 mg, 66%). MS ESI (+) m/z 406 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.47 (m, 2H), 7.39 (t,2H, J=7 Hz), 7.32 (t, 1H, J=7 Hz), 7.15 (m, 2H), 4.89 (q, 1H, J=6 Hz),3.18 (m, 1H), 2.84 (m, 2H), 2.42 (m, 1H), 1.92 (m, 1H), 1.58 (br, 2H),1.52 (d, 2H, J=6.7 Hz), 1.48 (d, 3H, J=6.7 Hz). Stereochemistry wasassigned by inference from(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 74

tert-Butyl2-((S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-yloxy)acetate

Prepared as previously described in Example 71 using tert-butyl2-bromoacetate in place of methyl iodide. MS ESI (+) m/z 520 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (m, 1H), 7.46 (d, 2H, J=8 Hz),7.34 (m, 2H), 7.27 (m, 1H), 7.13 (m, 2H), 4.93 (q, 1H, J=6 Hz), 4.18 (d,1H, J=16 Hz), 3.96 (d, 1H, J=16 Hz), 3.30 (m, 1H), 2.96 (m, 2H), 2.45(m, 1H), 2.01 (m, 1H), 1.63 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.46 (s, 9H).Stereochemistry was assigned by inference from(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 75

(R)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Prepared as previously described in Example 71 using(R)-2-(t-butyldiphenylsilyloxy)propanoic acid in place of(S)-2-(t-butyldiphenylsilyloxy)propanoic acid. MS ESI (+) m/z 420 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.46 (d, 2H, J=7 Hz),7.37 (t, 2H, J=8 Hz), 7.30 (t, 1H, J=7 Hz), 7.13 (m, 2H), 4.71 (q, 1H,J=6 Hz), 3.32 (s, 3H), 3.24 (m, 1H), 2.83 (m, 2H), 2.43 (m, 1H), 1.92(m, 1H), 1.51 (d, 3H, J=6 Hz), 1.45 (m, 1H). Stereochemistry wasassigned by comparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-oneand(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 76

(R)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Prepared as previously described in Example 75 using(R)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.MS ESI (+) m/z 420 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (m,1H), 7.44 (d, 2H, J=7 Hz), 7.35 (t, 2H, J=8 Hz), 7.29 (t, 1H, J=7 Hz),7.13 (m, 2H), 4.68 (q, 1H, J=6 Hz), 3.41 (s, 3H), 3.24 (m, 1H), 2.85 (m,2H), 2.43 (m, 1H), 1.95 (m, 1H), 1.54 (br, 3H), 1.46 (d, 3H, J=6 Hz).Stereochemistry was assigned by comparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-oneand(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 77

(S)-1-(S)-5-(2,5-difluorophenyl)-2-(3-(dimethylamino)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Prepared as previously described in Example 47 using(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-onein place of1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one.MS ESI (+) m/z 448 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (m,1H), 7.49 (d, 2H, J=7 Hz), 7.39 (m, 2H), 7.32 (m, 1H), 7.17 (m, 2H),4.73 (m, 1H), 3.44 (s, 3H), 3.26 (m, 1H), 2.56 (m, 1H), 2.49 (m, 2H),2.34 (s, 6H), 2.05 (m, 1H), 1.63 (m, 1H), 1.50 (d, 3H, J=7 Hz).

Example 78

Synthesis of(S)-1-((S)-5-(2,5-difluorophenyl)-2-(3-(methylamino)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Step A: Preparation of tert-butyl3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate:To a cooled (0° C.) solution of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one(50 mg, 0.12 mmol) in THF (2 mL) was added Boc-anhydride (31 mg, 0.14mmol). After warming slowly to room temperature and stirring for 64hours, the reaction mixture was concentrated under reduced pressure andchromatographed (DCM to 2% MeOH in DCM) to provide the product as acolorless oil (62 mg, 100%).

Step B: Preparation of(S)-1-((S)-5-(2,5-difluorophenyl)-2-(3-(methylamino)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one:To a cooled (0° C.) solution of tert-butyl3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate(62 mg, 0.12 mmol) in DMF (2 mL) was added methyl iodide (37 μL, 0.6mmol) followed by NaH (10 mg, 60%). After slowly warming to roomtemperature and stirring for 16 hours, the mixture was quenched withsaturated NH₄Cl (20 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organics were washed with water (5×20 mL) and brine (20 mL),and then dried over Na₂SO₄. The mixture was concentrated under reducedpressure and chromatographed (9:1 to 4:1 hexanes/ethyl acetate) toprovide the Boc-protected product (38 mg, 0.071 mmol). To this productwas added DCM (2 mL) and TFA (0.5 mL). After stirring at roomtemperature for 1 hour, the mixture was concentrated under reducedpressure and partitioned between saturated NaHCO₃ (10 mL) and ethylacetate (10 mL). The aqueous layer was extracted with ethyl acetate(2×10 mL). The combined organics were washed with NaHCO₃ (10 mL), brine(10 mL), dried over Na₂SO₄, and concentrated under reduced pressure toprovide a yellow oil. The oil was dissolved in ether (2 mL) and treatedwith 2N HCl in ether (2 mL). The mixture was stirred for 30 minutes,concentrated and triturated with ether to provide the di-HCl product asa yellow solid (31 mg, 51%). MS ESI (+) m/z 434 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.44 (d, 2H), 7.35 (m, 2H), 7.27 (m,1H), 7.12 (m, 2H), 4.68 (q, 1H, J=6 Hz), 3.40 (s, 3H), 3.25 (m, 1H),2.76 (m, 2H), 2.46 (s, 3H), 2.45 (m, 1H), 2.00 (m, 2H), 1.61 (m, 1H),1.45 (d, 3H, J=6 Hz).

Example 79

Synthesis of(S)-1-((S)-1-(3-((S)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylamino)-1-oxopropan-2-ylamino)-1-oxopropan-2-ylamine

To a solution of(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one(25 mg, 0.051 mmol) and Boc-Ala-Ala-OH (19.8 mg, 0.0766 mmol) in DMF (1mL) was added PyBOP (52.8 mg, 0.102 mmol) followed by DIEA (44 μL, 0.25mmol). After stirring at room temperature for 64 hours, the mixture waspartitioned between saturated NaHCO₃ (20 mL) and ethyl acetate. Theaqueous layer was extracted with ethyl acetate (10 mL). The combinedorganics were washed with water (5×10 mL), brine (10 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The orange residue waschromatographed (0-3% MeOH in DCM) to provide the Boc-protected productas a colorless glass (30 mg, 89%). To a cooled (0° C.) solution of thisproduct in DCM (2 mL) was added TFA (0.5 mL). After stirring for 5hours, the mixture was concentrated under reduced pressure andpartitioned between saturated NaHCO₃ (10 mL) and ethyl acetate. Theaqueous layer was extracted with ethyl acetate (10 mL) and the combinedorganics were washed with brine (10 mL), dried over Na₂SO₄, andconcentrated under reduced pressure to provide the product as acolorless glass (25 mg, 98%). MS ESI (+) m/z 562 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.79 (br, 1H), 7.50 (m, 1H), 7.42 (d, 2H, J=8 Hz),7.36 (t, 2H, J=7 Hz), 7.30 (t, 1H, J=7 Hz), 7.13 (m, 2H), 7.04 (t, 1H,J=5 Hz), 4.65 (q, 1H, J=6 Hz), 4.39 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H),3.36 (s, 3H), 3.23 (m, 1H), 3.07 (m, 1H), 2.24 (m, 1H), 1.96 (m, 1H),1.56 (m, 1H), 1.41 (d, 3H, J=7 Hz), 1.34 (d, 3H, J=7 Hz), 1.26 (m, 3H).

Example 80

Synthesis of1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one

Step A: Preparation of1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one:To a cooled (0° C.) solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(100 mg, 0.278 mmol) in DCM (5 mL) was added triethylamine (50.4 μL,0.362 mmol) followed by pivaloyl chloride (45 μL, 0.362 mmol). Afterwarming slowly to room temperature and stirring for 16 hours, themixture was partitioned between DCM (10 mL) and saturated NaHCO₃ (10mL). The aqueous layer was extracted with DCM (10 mL) and the combinedorganics were washed with brine (10 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was chromatographed(19:1 hexanes/ethyl acetate) to provide the product as a pale yellow oil(114 mg, 92%).

Step B: Preparation of1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one:To a solution of1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one(100 mg, 0.225 mmol) in MeOH (3 mL) was added 1N HCl/MeOH (1 mL)followed by 10% Pd/C (40 mg, wet, Degussa type). After stirring under aH₂ balloon for 3 hours, the mixture was filtered and concentrated underreduced pressure to provide the product as a white foam. MS ESI (+) m/z418 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (m, 1H), 7.43 (d, 2H,J=7 Hz), 7.35 (t, 2H, J=7 Hz), 7.25 (m, 1H), 7.11 (m, 2H), 3.47 (m, 1H),3.22 (m, 1H), 2.85 (m, 2H), 2.33 (m, 1H), 1.92 (m, 1H), 1.48 (m, 2H),1.39 (s, 9H).

Example 81

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(Enantiomer A)

Prepared as previously described in Example 80 using isobutyryl chloridein place of pivaloyl chloride. The1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-oneenantiomers were separated on a chiral column (Chiralcel OJ-H 250×10 mm)eluting with 1:1 EtOH/hexanes to provide the more polar enantiomer A andthe less polar enantiomer B. Reduction of the azide group of enantiomerA provided the final product. MS ESI (+) m/z 404 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.45 (d, 2H, J=8 Hz), 7.35 (t, 2H, J=7Hz), 7.25 (m, 1H), 7.11 (m, 2H), 3.48 (m, 1H), 3.22 (m, 1H), 2.87 (m,2H), 2.36 (m, 1H), 1.95 (m, 1H), 1.57 (m, 3H), 1.18 (dd, 6H, J=11 Hz, 6Hz).

Example 82

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one(Enantiomer B)

Prepared as in Example 81 using the less polar enantiomer B. MS ESI (+)m/z 404 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (m, 1H), 7.45 (d,2H, J=8 Hz), 7.35 (t, 2H, J=8 Hz), 7.28 (m, 1H), 7.10 (m, 2H), 3.48 (m,1H), 3.24 (m, 1H), 2.88 (m, 2H), 2.36 (m, 1H), 2.11 (br, 2H), 1.96 (m,1H), 1.57 (m, 1H), 1.18 (dd, 6H, J=7 Hz, 13 Hz).

Example 83

Synthesis of(S)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Step A: Preparation of 2-(methoxymethoxy)-1-phenylethanone: To a cooled(0° C.) solution of 2-hydroxyacetophenone (1.0 g, 7.3 mmol) in DMF (50mL) was added lithium hydride (74 mg, 95%, 8.8 mmol). After stirring for30 minutes, MOM-Cl (0.73 mL, 9.5 mmol) was added slowly via syringe andthe mixture was allowed to warm slowly to room temperature and wasstirred for 16 hours. The reaction mixture was treated with saturatedNH₄Cl (100 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganics were washed with water (6×50 mL) and brine (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The brown residue waschromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide theproduct as a colorless oil (0.60 g, 45%).

Step B: Preparation of5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole:To a solution of 2-(methoxymethoxy)-1-phenylethanone (0.60 g, 3.33 mmol)in EtOH/DCM (3:1, 12 mL) was added 2,5-difluorobenzothiohydrazide (0.63g, 3.33 mmol). After stirring at room temperature for 16 hours, themixture was concentrated under reduced pressure. The brown residue waschromatographed (9:1 hexanes/ethyl acetate) to provide the product as ayellow oil (0.73 g, 63%).

Step C: Preparation of(S)-2-(t-butyldiphenylsilyloxy)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one:To a solution of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid (0.70g, 2.14 mmol) in DMF (20 mL) was added5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(0.50 g, 1.43 mmol) followed by PyBOP (1.11 g, 2.14 mmol) and DIEA (497μL, 2.85 mmol). After stirring at room temperature for 16 hours, themixture was treated with saturated NaHCO₃ (50 mL) and extracted withethyl acetate (3×30 mL). The combined organics were washed with water(6×30 mL) and brine (30 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The yellow residue was chromatographed (19:1 to 9:1hexanes/ethyl acetate) to afford the less polar diastereomer(S)-2-(tert-butyldiphenylsilyloxy)-1-(R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one(110 mg, 12%), and the more polar diastereomer(S)-2-(tert-butyldiphenylsilyloxy)-1-(S)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one(146 mg of a 1:1 mixture with starting material) as yellow oils.Absolute stereochemistry was assigned by inference from(S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Step D: Preparation of(S)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one:To a cooled (0° C.) solution of(S)-2-(tert-butyldiphenylsilyloxy)-1-(R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one(110 mg, 0.17 mmol) in THF (10 mL) was added TBAF (0.28 mL, 1.0 M, 0.28mmol). After slowly warming to room temperature and stirring for 16hours, the mixture was treated with 0.5 N HCl (30 mL) and extracted withethyl acetate (2×30 mL). The combined organics were washed with NaHCO₃(30 mL) and brine (30 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The pale yellow residue was chromatographed (9:1 to4:1 hexanes/ethyl acetate) to provide the product as a white solid(0.045 g, 64%).

Step E: Preparation of(S)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one:To a cooled (0° C.) solution of(S)-1-(R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one(45 mg, 0.11 mmol) in DMF was added methyl iodide (100 μL, 1.6 mmol)followed by sodium hydride (10 mg). After slowly warming to roomtemperature and stirring for 16 hours, the mixture was treated withsaturated NH₄Cl (10 mL) and extracted with ethyl acetate (2×10 mL). Thecombined organics were washed with water (6×10 mL) and brine (10 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The paleyellow residue was chromatographed (4:1 to 2:1 hexanes/ethyl acetate) toprovide the product as a pale yellow oil (0.040 g, 86%). MS ESI (+) m/z437 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m, 1H), 7.42 (m,2H), 7.35 (m, 2H), 7.29 (m, 1H), 7.12 (m, 2H), 4.80 (s, 2H), 4.78 (d,1H, J=10 Hz), 4.71 (q, 1H, J=7 Hz), 4.59 (d, 1H, J=10 Hz), 3.43 (s, 3H),3.39 (s, 3H), 1.48 (d, 3H, J=7 Hz). Stereochemistry was assigned byinference from(S)-1-(R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 84

(S)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

Prepared as previously described in Example 83 using(S)-2-(tert-butyldiphenylsilyloxy)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-onefrom Step C. MS ESI (+) m/z 437 (M+1) detected; ¹H NMR (400 MHz, CDCl₃)δ 7.53 (m, 1H), 7.43 (m, 2H), 7.37 (m, 2H), 7.31 (m, 1H), 7.11 (m, 2H),4.76 (m, 4H), 4.47 (d, 1H, J=10 Hz), 3.41 (s, 3H), 3.35 (s, 3H), 1.47(d, 3H, J=7 Hz). Stereochemistry was assigned by inference from(S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 85

Synthesis of(S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

To a solution of(S)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one(16 mg, 0.037 mmol) in MeOH (2 mL) was added HCl (300 μL of 6 Msolution). After stirring at 50° C. for 5 hours, the mixture was cooledto room temperature and partitioned between saturated NaHCO₃ (20 mL) andethyl acetate (10 mL). The aqueous phase was extracted with ethylacetate (2×10 mL). The combined organics were washed with brine (10 mL),dried over Na₂SO₄, and concentrated under reduced pressure. The paleyellow residue was chromatographed (9:1 to 2:1 hexanes/ethyl acetate) toprovide the product as a colorless gum (4.2 mg, 29%). MS ESI (+) m/z 393(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (m, 1H), 7.37 (m, 5H),7.13 (m, 2H), 4.74 (m, 2H), 4.48 (d, 1H, J=11 Hz), 4.19 (d, 1H, J=10Hz), 3.44 (s, 3H), 1.59 (m, 3H). Absolute stereochemistry was assignedby examination of a protein:inhibitor co-crystal structure of Eg5 and(S)-1-(R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 86

Synthesis of1-(2-(3-aminopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one

Step A: Preparation of N′-(4-azido-1-phenylbutylidene)-5-chloro-2-methylbenzohydrazide: To a solution of 5-chloro-2-methylbenzohydrazide (2.70g, 14.62 mmol) prepared as in Example 1, Step B, in toluene (100 mL) wasadded 4-azido-1-phenylbutan-1-one (3.04 g, 16.1 mmol) prepared as inExample 70, Step A, followed by p-toluenesulfonic acid monohydrate (0.28g, 1.46 mmol). The reaction was heated to reflux and stirred under aDean-Stark trap for 16 hours. The cooled mixture was diluted with EtOAc(300 mL) and washed with NaHCO₃ (100 mL). The aqueous layer wasextracted with EtOAc (100 mL) and the combined organics were washed withbrine (100 mL), dried over Na₂SO₄ and concentrated. The residue wastriturated with ether and filtered to afford the product (3.09 g, 59%)as a tan solid.

Step B: Preparation of1-(2-(3-azidopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one:To a solution of N′-(4-azido-1-phenylbutylidene)-5-chloro-2-methylbenzohydrazide (100 mg, 0.28 mmol) in pyridine (1 mL) was added pivaloylchloride (70 μL, 0.56 mmol). After stirring at room temperature for 16hours the heterogeneous mixture was treated with water (10 mL) andextracted with EtOAc (3×10 mL). The combined organic phases were washedsuccessively with 10% NaHSO₄ (2×10 mL), NaHCO₃ (10 mL) and brine (10 mL)then dried over Na₂SO₄ and concentrated. The residue was purified bypreparative TLC (9:1 hexanes/EtOAc) to afford the product (62 mg, 50%)as a colorless oil.

Step C: Preparation of1-(2-(3-aminopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one:To a solution of1-(2-(3-azidopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one(62 mg, 0.141 mmol) in methanol (2 mL) was added PtO₂ (5 mg) followed by1N HCl/MeOH (0.42 mL, 0.42 mmol). The mixture was hydrogenated under aballoon atmosphere for 4 hours then filtered through GF paper and thefiltrate concentrated. The residue was purified by flash columnchromatography (CH₂Cl₂ to 3% MeOH/CH₂Cl₂ to 10%) to afford the di-HClproduct which was triturated with hexanes and filtered to afford a whitesolid (18 mg, 26%). MS ESI (+) m/z 414 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 7.74 (s, 1H), 7.54 (d, 2H, J=7 Hz), 7.33 (m, 4H), 7.22 (d, 1H,J=9 Hz), 3.36 (m, 1H), 3.08 (m, 1H), 2.99 (m, 1H), 2.63 (s, 3H), 2.46(m, 1H), 1.78 (m, 2H), 1.33 (s, 9H).

The following examples were prepared using the appropriately substitutedbenzohydrazides, ketones and acid chlorides:

Example 87

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(phenyl)methanonedihydrochloride

MS ESI (+) m/z 421.9 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d,2H, J=8 Hz), 7.67 (d, 2H, J=8 Hz), 7.46 (m, 1H), 7.36 (m, 6H), 7.12 (m,2H), 3.37 (m, 1H), 3.00 (brs, 2H), 2.63 (m, 1H), 1.86 (m, 2H).

Example 88

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 402 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m,2H), 7.45 (m, 1H), 7.33 (m, 3H), 7.14 (m, 2H), 3.29 (m, 1H), 3.04 (m,2H), 2.51 (m, 1H), 1.79 (m, 2H), 1.33 (s, 9H).

Example 89

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-3-methylbutan-1-onedihydrochloride

MS ESI (+) m/z 402 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d,2H, J=8 Hz), 7.51 (m, 1H), 7.34 (m, 3H), 7.15 (t, 2H, J=8 Hz), 3.20 (m,1H), 3.02 (m, 2H), 2.64 (m, 2H), 2.49 (m, 1H), 2.11 (m, 1H), 1.82 (m,2H), 0.89 (t, 6H, J=7 Hz).

Example 90

1-(2-(3-aminopropyl)-5-(5-chloro-2-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-onedihydrochloride

MS ESI (+) m/z 404.4 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (m,1H), 7.57 (m, 2H), 7.41 (m, 1H), 7.35 (m, 3H), 7.13 (t, 1H, J=9), 3.31(m, 1H), 3.21 (m, 1H), 3.04 (brs, 2H), 2.56 (m, 1H), 1.80 (m, 2H), 1.17(d, 3H, J=7 Hz), 1.07 (d, 3H, J=7 Hz).

Example 91

1-(2-(3-aminopropyl)-5-(2-chloro-5-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-onedihydrochloride

MS ESI (+) m/z 404 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (m,3H), 7.45 (m, 1H), 7.33 (m, 3H), 7.11 (m, 1H), 3.30 (m, 1H), 3.21 (m,1H), 3.06 (brs, 2H), 2.58 (m, 1H), 1.83 (m, 2H), 1.19 (d, 3H, J=7 Hz),1.09 (d, 3H, J=7 Hz).

Example 92

1-(2-(3-aminopropyl)-5-(2,5-dichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-onedihydrochloride

MS ESI (+) m/z 420 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d,1H, J=2 Hz), 7.57 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=8 Hz), 7.34 (m, 4H),3.30 (m, 2H), 3.21 (m, 1H), 3.07 (brs, 1H), 2.57 (m, 1H), 1.82 (m, 2H),1.19 (d, 3H, J=7 Hz), 1.09 (d, 3H, J=7 Hz).

Example 93

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(cyclopropyl)methanonedihydrochloride

MS ESI (+) m/z 386 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (m,2H), 7.52 (m, 1H), 7.36 (m, 3H), 7.16 (m, 2H), 3.02 (m, 1H), 2.84 (brs,2H), 2.58 (m, 3H), 1.65 (m, 2H), 1.05 (m, 1H), 1.05 (m, 1H), 0.98 (m,1H), 0.87 (m, 2H).

Example 94

1-(2-(3-aminopropyl)-5-(2-chloro-5-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 418 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m,3H), 7.47 (m, 1H), 7.33 (m, 3H), 7.10 (m, 1H), 3.28 (m, 1H), 3.02 (m,2H), 2.52 (m, 1H), 1.79 (m, 2H), 1.35 (s, 9H).

Example 95

1-(2-(3-aminopropyl)-5-(2,5-dichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 435 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d,1H, J=2 Hz), 7.55 (d, 2H, J=6), 7.40 (d, 1H, J=9 Hz), 7.34 (m, 4H), 3.32(m, 1H), 3.08 (m, 1H), 3.00 (m, 1H), 2.50 (m, 1H), 1.79 (m, 2H), 1.35(s, 9H).

Example 96

1-(2-(3-aminopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-onedihydrochloride

MS ESI (+) m/z 400 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (s,1H), 7.56 (d, 2H, J=8 Hz), 7.33 (m, 4H), 7.22 (d, 1H, J=9 Hz), 3.26 (m,2H), 3.03 (m, 2H), 2.58 (s, 3H), 2.53 (m, 1H), 1.80 (m, 2H), 1.18 (d,3H, J=7 Hz), 1.07 (d, 3H, J=7 Hz).

Example 97

1-(2-(3-aminopropyl)-5-(2-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 452 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d,1H, J=6 Hz), 7.73 (m, 1H), 7.55 (d, 2H, J=6 Hz), 7.34 (m, 4H), 3.38 (m,1H), 3.12 (m, 1H), 3.01 (m, 1H), 2.48 (m, 1H), 1.82 (m, 2H), 1.34 (s,9H).

Example 98

1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 372 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (m,3H), 7.46 (d, 1H, J=6 Hz), 7.32 (m, 3H), 7.07 (m, 1H), 3.20 (m, 1H),2.95 (m, 2H), 2.50 (m, 1H), 1.72 (m, 2H), 1.33 (s, 9H).

Example 99

1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-3-yl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 372 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d,1H, J=3 Hz), 7.53 (d, 2H, J=6 Hz), 7.48 (d, 1H, J=5 Hz), 7.33 (m, 4H),3.24 (m, 1H), 2.99 (brs, 2H), 2.48 (m, 1H), 1.73 (m, 2H), 1.33 (s, 9H).

Example 100

1-(2-(3-aminopropyl)-5-(5-chlorothiophen-2-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one

MS ESI (+) m/z 406 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d,2H, J=9 Hz), 7.33 (m, 3H), 7.30 (d, 1H, J=4 Hz), 6.89 (d, 1H, J=4 Hz),3.23 (m, 1H), 2.95 (m, 2H), 2.47 (m, 1H), 1.72 (m, 2H), 1.31 (s, 9H).

Example 101

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(4-fluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 420 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m,2H), 7.45 (m, 1H), 7.15 (m, 2H), 7.02 (m, 2H), 3.19 (m, 1H), 2.97 (brs,2H), 2.48 (m, 1H), 1.70 (m, 2H), 1.34 (s, 9H).

Example 102

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-p-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydro chloride

MS ESI (+) m/z 416 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (m,3H), 7.13 (m, 4H), 3.26 (m, 1H), 3.04 (m, 2H), 2.51 (m, 1H), 2.29 (s,3H), 1.78 (m, 2H), 1.33 (s, 9H).

Example 103

1-(2-(3-aminopropyl)-2-(4-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 436 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d,2H, J=9 Hz), 7.44 (m, 1H), 7.30 (d, 2H, J=9 Hz), 7.15 (m, 2H), 3.25 (m,1H), 3.01 (m, 2H), 2.48 (m, 1H), 1.74 (m, 2H), 1.33 (s, 9H).

Example 104

1-(2-(3-aminopropyl)-2-(4-bromophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 480 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (m,5H), 7.15 (m, 2H), 3.28 (m, 1H), 3.05 (brs, 2H), 2.48 (m, 1H), 1.77 (m,2H), 1.33 (s, 9H).

Example 105

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3,4-dimethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 429.9 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m,1H), 7.30 (s, 1H), 7.25 (m, 1H), 7.10 (m, 3H), 3.25 (m, 1H), 3.04 (m,2H), 2.50 (m, 1H), 2.22 (s, 3H), 2.19 (s, 3H), 1.80 (m, 2H), 1.33 (s,9H).

Example 106

1-(2-(3-aminopropyl)-2-(4-tert-butylphenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 458 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d,2H, J=9 Hz), 7.41 (m, 1H), 7.34 (d, 2H, J=9 Hz), 7.12 (m, 2H), 3.29 (m,1H), 3.04 (brs, 2H), 2.52 (m, 1H), 1.78 (m, 2H), 1.35 (s, 9H), 1.24 (s,9H).

Example 107

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-m-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 416 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m,1H), 7.32 (d, 2H, J=9 Hz), 7.22 (t, 1H, J=7 Hz), 7.13 (m, 3H), 3.25 (m,1H), 3.04 (brs, 2H), 2.50 (m, 1H), 2.33 (s, 3H), 1.78 (m, 2H), 1.33 (s,9H).

Example 108

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3,5-dimethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-onedihydrochloride

MS ESI (+) m/z 429.9 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45 (m,1H), 7.14 (m, 4H), 6.95 (s, 1H), 3.24 (m, 1H), 3.04 (m, 2H), 2.49 (m,1H), 2.28 (s, 6H), 1.99 (m, 2H), 1.33 (s, 9H).

Example 109

Synthesis ofN-(3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl)propyl)isobutyramide

To a solution of1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-onedihydrochloride, prepared as in the above examples, (50 mg, 0.11 mmol)in anhydrous CH₂Cl₂ (1 mL) was added DIEA (95 μL, 0.54 mmol) followed byisobutyryl chloride (17 μL, 0.16 mmol). After stirring at roomtemperature for 16 hours the mixture was treated with 1N HCl (10 mL) andextracted with CH₂Cl₂ (2×10 mL). The combined organic phases were washedwith brine (10 mL) then dried over Na₂SO₄ and concentrated. The residuewas chromatographed (4:1 to 2:1 hexanes/EtOAc) to afford the product (31mg, 62%) as a colorless gum. MS ESI (+) m/z 458.1 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.55 (m, 3H), 7.36 (m, 3H), 7.17 (m, 2H), 3.33 (m,3H), 3.04 (m, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 1.77 (m, 1H), 1.56 (m,1H), 1.16 (m, 12H).

Example 110

N-(3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl)propyl)methanesulfonamide

Prepared as in Example 109 using methanesulfonyl chloride in place ofisobutyryl chloride. MS ESI (+) m/z 466.1 (M+1) detected; ¹H NMR (400MHz, CDCl₃) δ 7.51 (m, 3H), 7.38 (m, 3H), 7.17 (m, 2H), 3.41 (m, 1H),3.21 (m, 2H), 3.04 (m, 1H), 2.95 (s, 3H), 2.59 (m, 1H), 1.74 (m, 2H),1.21 (d, 3H, J=6.8 Hz), 1.15 (d, 3H, J=6.8 Hz).

Example 111

Synthesis of(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one

Step A: Preparation of (S)-2-methoxypropanoic anhydride: To a solutionof (S)-2-methoxy propanoic acid (0.25 g, 4.80 mmol) in CH₂Cl₂ (2 mL) wasadded EDCI (0.46 g, 2.38 mmol). After stirring at room temperature for 1hour, hexanes were added and the mixture filtered to obtain the product(0.24 g, 53%).

Step B: Preparation of(2S)-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one:To a solution ofN′-(4-azido-1-phenylbutylidene)-2,5-difluorobenzohydrazide (100 mg, 0.29mmol), prepared as in Example 85, Step A, in DCE (1 mL) was added(S)-2-methoxypropanoic anhydride from the previous step (277 mg, 1.46mmol). After stirring at reflux for 48 hours the crude mixture waschromatographed (CH₂Cl₂ to 2.5% MeOH/CH₂Cl₂) to afford the product (81mg, 65%) as a clear oil.

Step C: Preparation of(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one:(2S)-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one(50 mg, 0.11 mmol) was reduced as in Example 86, Step C, to afford theproduct (32 mg, 68%) as a colorless oil. MS ESI (+) m/z 404 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 7.62 (m, 1H), 7.56 (m, 1H), 7.52 (m,1H), 7.34 (m, 3H), 7.17 m, 2H), 4.58 (q, 0.5H, J=7 Hz), 4.52 (q, 0.5H,J=7 Hz), 3.38 (s, 1.5H), 3.22 (s, 1.5H), 3.10 (m, 2H), 2.60 (m, 1H),1.90 (m, 3H), 1.49 (d, 1.5H, J=7 Hz), 1.27 (d, 1.5H, J=7 Hz). 1:1mixture of diastereomers.

Example 112

(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxybutan-1-one

Prepared as in Example 71 using(S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of(S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (m, 3H), 7.35 (app t, 2H,J=8 Hz), 7.28 (m, 1H), 7.13 (m, 2H), 4.53 (dd, 1H, J=7 Hz, 4 Hz), 3.40(s, 3H), 3.26 (m, 1H), 2.86 (m, 2H), 2.42 (m, 1H), 1.94 (m, 2H), 1.74(m, 2H), 0.96 (t, 3H, J=8 Hz). Stereochemistry was assigned bycomparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 113

(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxybutan-1-one

Prepared as in Example 71 using(S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of(S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.46 (m, 3H), 7.36 (app t, 2H,J=8 Hz), 7.13 (m, 2H), 4.54 (dd, 1H, J=8 Hz, 4 Hz), 3.31 (s, 3H), 3.23(m, 1H), 2.84 (m, 2H), 2.44 (m, 1H), 1.94 (m, 2H), 1.78 (m, 1H), 1.48(m, 1H), 1.08 (t, 3H, J=7 Hz). Stereochemistry was assigned bycomparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 114

(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-3-methylbutan-1-one

Prepared as in Example 71 using2-(tert-butyldiphenylsilyloxy)-3-methylbutanoic acid in place of(S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. Product obtained as a2:1 mixture of diastereomers. MS APCI (+) m/z 448 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.49 (m, 3H), 7.35 (m, 2H), 7.29 (m, 1H), 7.13 (m,2H), 4.45 (d, 0.33H, J=5 Hz), 4.10 (d, 0.66H, J=5 Hz), 3.39 (s, 2H),3.27 (m, 2H), 2.87 (m, 2H), 2.44 (m, 1H), 2.22 (m, 1H), 1.95 (m, 1H),1.53 (m, 1H), 1.09 (d, 0.85H, J=7 Hz), 0.99 (m, 3H), 0.82 (d, 2.15H, J=7Hz).

Example 115

(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-3-methylbutan-1-one

Prepared as in Example 71 using2-(tert-butyldiphenylsilyloxy)-3-methylbutanoic acid in place of(S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 448(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (m, 3H), 7.35 (m, 2H),7.28 (m, 1H), 7.12 (m, 2H), 4.45 (d, 1H, J=4 Hz), 3.27 (s, 3H), 3.25 (m,1H), 2.87 (m, 2H), 2.49 (m, 1H), 2.23 (m, 1H), 1.97 (m, 1H), 1.52 (m,1H), 1.09 (d, 3H, J=7 Hz), 0.99 (d, 3H, J=7 Hz). Stereochemistry wasassigned by comparison to(S)-1-(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 116

(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxybutan-1-one

Prepared as in Example 73. MS APCI (+) m/z 420 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.50 (m, 3H), 7.38 (m, 2H), 7.32 (m, 1H), 7.14 (m,2H), 4.78 (dd, 1H, J=7 Hz, 4 Hz), 3.19 (m, 1H), 2.86 (m, 2H), 2.41 (m,1H), 1.98 (m, 2H), 1.64 (m, 2H), 0.96 (t, 3H, J=7 Hz). Stereochemistrywas assigned by comparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 117

(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxybutan-1-one

Prepared as in Example 73. MS APCI (+) m/z 420 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.45 (m, 3H), 7.38 (app t, 2H, J=8 Hz), 7.31 (m, 1H),7.14 (m, 2H), 4.77 (dd, 1H, J=7 Hz, 3 Hz), 3.16 (m, 1H), 2.85 (m, 2H),2.49 (m, 1H), 1.99 (m, 2H), 1.70 (m, 2H), 1.07 (t, 3H, J=7 Hz).Stereochemistry was assigned by comparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 118

(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one

Prepared as in Example 73. Product obtained as a 2:1 mixture ofdiastereomers. MS APCI (+) m/z 434 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 7.49 (m, 3H), 7.38 (app t, 2H, J=8 Hz), 7.32 (m, 1H), 7.15 (m,2H), 4.71 (m, 1H), 3.20 (m, 1H), 2.86 (m, 2H), 2.41 (m, 2H), 1.92 (m,1H), 1.51 (m, 1H), 1.14 (d, 1H, J=7 Hz), 1.12 (m, 3H), 0.87 (d, 1.4H,J=7 Hz), 0.66 (d, 1.6H, J=6 Hz).

Example 119

(S)-1-((R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one

Prepared as in Example 73. MS APCI (+) m/z 434 (M+1) detected; ¹H NMR(400 MHz, CDCl₃) δ 7.46 (m, 3H), 7.34 (app t, 2H, J=8 Hz), 7.26 (m, 1H),7.11 (m, 2H), 4.65 (d, 1H, J=3 Hz), 3.24 (m, 1H), 2.98 (t, 2H, J=6 Hz),2.64 (m, 1H), 2.28 (m, 1H), 2.12 (m, 1H), 1.66 (m, 1H), 1.08 (d, 3H, J=7Hz), 0.86 (d, 3H, J=7 Hz). Stereochemistry was assigned by comparison to(S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Example 120

2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(Enantiomer A)

Prepared as previously described in Example 68. The tert-butyl3-(5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamateenantiomers were separated on a chiral column (Chiralcel ODH 250×20 mm)eluting with 2% EtOH/hexanes to provide the less polar enantiomer A andthe more polar enantiomer B. Boc-deprotection of enantiomer A providedthe final product. MS ESI (+) m/z 421 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 8.44 (br, 3H), 7.52 (m, 3H), 7.34 (m, 2H), 7.24 (m, 1H), 7.08(m, 2H), 3.35 (m, 1H), 3.16 (s, 3H), 3.06 (m, 2H), 2.42 (m, 1H), 2.13(m, 1H), 1.88 (m, 1H), 1.61 (s, 3H).

Example 121

2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(Enantiomer B)

Prepared as in Example 120 using the more polar enantiomer, B. MS ESI(+) m/z 421 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (br, 3H),7.52 (m, 3H), 7.34 (m, 2H), 7.24 (m, 1H), 7.08 (m, 2H), 3.35 (m, 1H),3.16 (s, 3H), 3.06 (m, 2H), 2.42 (m, 1H), 2.13 (m, 1H), 1.88 (m, 1H),1.61 (s, 3H).

Example 122

Synthesis of2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

Step A: Preparation of(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-imidazol-1-yl)methanone:To a solution of2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole(0.492 g, 1.37 mmol) in THF (8 mL) was added 1,1′-carbonyl diimidazole(0.266 g, 1.64 mmol). After stirring at 75° C. for 2 hours, the reactionmixture was concentrated under reduced pressure and dissolved indichloromethane (20 mL). The solution was washed with HCl (0.5 M), driedover Na₂SO₄ and concentrated to provide the crude product.

Step B: Preparation of(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(3-methylimidazoliumiodide-1-yl)methanone: To a solution of(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1H-imidazol-1-yl)methanone(0.621 g, 1.37 mmol) in acetonitrile (5 mL) was added iodomethane (0.972g, 6.85 mmol). After stirring in a sealed flask for 24 hours, themixture was concentrated to provide the crude product.

Step C: Preparation of2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide:To a solution of(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(3-methylimidazoliumiodide-1-yl)methanone (0.112 g, 0.188 mmol) andO-(tert-buty)hydroxylamine hydrochloride (0.047 g, 0.376 mmol) indichloromethane (3 mL) was added triethylamine (0.095 g, 0.941 mmol).After stirring for 1 hour, the mixture was concentrated under reducedpressure and chromatographed (10:1 hexanes/ethyl acetate) to provide theproduct (0.078 g, 87%).

Step D: Preparation of2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide:To a cooled (0° C.) solution of2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(0.061 g, 0.13 mmol) and iodomethane (0.18 g, 1.3 mmol) in DMF (4 mL)was added sodium hydride (0.006 g, 0.26 mmol). After stirring at 0° C.for 30 minutes and then at room temperature for 1 hour, the mixture waspartitioned between ethyl acetate (10 mL) and saturated NH₄Cl (5 mL).The organic layer was washed with water (2×5 mL), dried and concentratedunder reduced pressure to provide the crude product.

Step E: Preparation of2-(3-aminopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide:To a solution of2-(3-azidopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(0.032 g, 0.065 mmol) and platinum oxide (15 mg) in methanol (3 mL) wasadded HCl (5.3 M solution in dioxane, 0.05 mL). After stirring under ahydrogen balloon for 1 hour, the mixture was filtered and the filtratewas concentrated under reduced pressure to provide the product.

Step F: Preparation of2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide:To2-(3-aminopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(0.023 g, 0.05 mmol) was added TFA (2 mL). After stirring for 18 hours,the mixture was concentrated and chromatographed (10:1:0.2dichloromethane/methanol/30% NH₄OH) to provide the product (0.01 g,49%). MS ESI (+) m/z 407 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 7.45(d, 2H), 7.36 (m, 3H), 7.29 (m, 1H), 7.11 (m, 2H), 3.28 (s, 3H), 3.12(m, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.24 (m, 1H), 1.98 (m, 1H), 1.62(m, 1H).

The following compounds are prepared by using the procedures describedabove, utilizing the appropriately substituted reagents.

R¹ Name

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(pyridin-3-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(pyridin-2-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(3-methylfuran-2-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(2-methylthiazol-5-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(5-methylthiophen-2-yl)methanone

(3-aminophenyl)(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)methanone

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)propan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)butan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylbutan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-ethylbutan-1-one

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(cyclobutyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(cyclopentyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(tetrahydrofuran-2-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(2-fluorocyclohexyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(1-methylcyclopropyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(1-(trifluoromethyl)cyclopropyl)methanone

(2R)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxypropan-1-one

(2R)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxybutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxybutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxy-3-methylbutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxy-3,3-dimethylbutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-cyclopropyl-2-hydroxyethanone

(2S)-2-amino-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-cyclopropylethanone

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-cyclopropyl-2-(methylamino)ethanone

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-ethoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(trifluoromethoxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-cyclopropoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxy-3-methylbutan-1-one

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(1-hydroxycyclopropyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)(1-methoxycyclopropyl)methanone

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-hydroxy-2-methylpropan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxy-2-methylpropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one

(2R)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxybutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxy-3,3-dimethylbutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-isobutoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-isopropoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-tert-butoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(2-methoxyethoxy)propan-1-one

(2S)-1-(2-(3-amino-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-phenoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(pyridin-2-yloxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(pyridin-3-yloxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(benzyloxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxy-2-phenylethanone

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-3-methoxypropan-1-one

N-((S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-3-methyl-1-oxobutan-2-yl)acetamide

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)propane-1,2-dione

(Z)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(hydroxyimino)propan-1-one

(Z)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-(methoxyimino)propan-1-one

Ar² R¹ Name 4-methylphenyl (S)-1- (2S)1-(2-(3-aminopropyl)-5-(2,5-methoxyethyl difluorophenyl)-2-p-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 4-chlorophenyl (S)-1-1-(2-(3-aminopropyl)-2-(4-chlorophenyl)-5- methoxyethyl(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one4-bromophenyl (S)-1- 1-(2-(3-aminopropyl)-2-(4-bromophenyl)-5-methoxyethyl (2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 4-t-butylphenyl (S)-1-1-(2-(3-aminopropyl)-2-(4-tert-butylphenyl)- methoxyethyl5-(2,5-difluorophenyl)-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one3,4-dimethylphenyl (S)-1- 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-methoxyethyl 2-(3,4-dimethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one 3-methylphenyl (S)-1-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- methoxyethyl2-m-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one3,5-dimethylphenyl (S)-1- 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-methoxyethyl 2-(3,5-dimethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 2-chlorophenyl t-butyl1-(2-(3-aminopropyl)-2-(2-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one2-ethylphenyl t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(2-ethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)- 2,2-dimethylpropan-1-one3-nitrophenyl t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-nitrophenyl)-1,3,4-oxadiazol-3(2H)-yl)- 2,2-dimethylpropan-1-one3-hydroxyphenyl t-butyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one3-aminophenyl t-butyl 1-(2-(3-aminophenyl)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one3-carboxyphenyl t-butyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-pivaloyl-2,3-dihydro-1,3,4-oxadiazol-2- yl)benzoic acid 3-cyanophenylt-butyl 4-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-pivaloyl-2,3-dihydro-1,3,4-oxadiazol-2- yl)benzonitrile3,4-dichlorophenyl t-butyl 1-(2-(3-aminopropyl)-2-(3,4-dichlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one 3-fluorophenyl t-butyl1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-fluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one3-chlorophenyl t-butyl 1-(2-(3-aminopropyl)-2-(3-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)- yl)-2,2-dimethylpropan-1-one4-fluorophenyl (S)-2- (2S)-1-(2-(3-aminopropyl)-5-(2,5- methoxyethyldifluorophenyl)-2-(4-fluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 3-fluorophenyl (S)-2-(2S)-1-(2-(3-aminopropyl)-5-(2,5- methoxyethyldifluorophenyl)-2-(3-fluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 2-chlorophenyl (S)-2-(2S)-1-(2-(3-aminopropyl)-2-(2- methoxyethylchlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one 3-methylphenyl iso-Propyl1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-m-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one 3-ethylphenyliso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-ethylphenyl)-1,3,4-oxadiazol-3(2H)-yl)- 2-methylpropan-1-one3-pyridyl iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one5-methylthiophen-2-yl iso-Propyl1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(5-methylthiophen-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one 1-methyl-1H- iso-Propyl1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)- imidazol-2-yl)2-(1-methyl-1H-imidazol-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one 2-methylthiazol-4-yl iso-Propyl1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(2-methylthiazol-4-yl)-1,3,4-oxadiazol- 3(2H)-yl)-2-methylpropan-1-one2-methylphenyl iso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-o-tolyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one 2-pyridyliso-Propyl 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(pyridin-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one2-(1H-imidazol-4-yl)- iso-Propyl1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(1H-imidazol-4-yl)-1,3,4-oxadiazol-3(2H)- yl)-2-methylpropan-1-one3-amino-1H-pyrazol- iso-Propyl 1-(2-(3-amino-1H-pyrazol-5-yl)-2-(3- 5-ylaminopropyl)-5-(2,5-difluorophenyl)-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one

NR²R³ Ar¹ Name NH₂ 2-fluorophenyl1-(2-(3-aminopropyl)-5-(2-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one NH₂2-chlorophenyl 1-(2-(3-aminopropyl)-5-(2-chlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methylpropan-1-one NH-Ala-Ala 2,5-difluorophenyl NHC(═O)(CH₂)₂NMe₂ 2,5-N-(3-(5-(2,5-difluorophenyl)-3-isobutyryl-2- difluorophenylphenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-(dimethylamino)propanamide

2,5- difluorophenyl 1-(5-(2,5-difluorophenyl)-2-phenyl-2-(3-(pyrrolidin-1-yl)propyl)-1,3,4-oxadiazol-3(2H)- yl)-2-methylpropan-1-one

2,5- difluorophenyl 1-(5-(2,5-difluorophenyl )-2-phenyl-2-(3-(piperidin-1-yl)propyl)-1,3,4-oxadiazol-3(2H)- yl)-2-methylpropan-1-one

2,5- difluorophenyl 1-(5-(2,5-difluorophenyl)-2-(3-(4-methylpiperazin-1-yl)propyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one

R¹ Ar¹ Name t-butyl 2-fluorophenyl1-(2-(3-aminopropyl)-5-(2-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl2-chlorophenyl 1-(2-(3-aminopropyl)-5-(2-chlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl3-fluorophenyl 1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl3-chlorophenyl 1-(2-(3-aminopropyl)-5-(3-chlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one t-butyl2-fluoro-5- 1-(2-(3-aminopropyl)-5-(5-chloro-2- chlorophenylfluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one t-butyl 2-chloro-5-1-(2-(3-aminopropyl)-5-(2-chloro-5- methylphenylmethylphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one t-butyl 2-trifluoro1-(2-(3-aminopropyl)-5-(5-fluoro-2- methyl-5-(trifluoromethyl)phenyl)-2-phenyl-1,3,4- fluorophenyloxadiazol-3(2H)-yl)-2,2-dimethylpropan-1- one (S)-2-methoxyethyl2-chloro-5- (2S)-1-(2-(3-aminopropyl)-5-(2-chloro-5- fluorophenylfluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one(S)-2-methoxyethyl 2,5- (2S)-1-(2-(3-aminopropyl)-5-(2,5- dichlorophenyldichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 2-chlorophenyl(2S)-1-(2-(3-aminopropyl)-5-(2- chlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 2-fluorophenyl(2S)-1-(2-(3-aminopropyl)-5-(2- fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 3-chlorophenyl(2S)-1-(2-(3-aminopropyl)-5-(3- chlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 3-fluorophenyl(2S)-1-(2-(3-aminopropyl)-5-(3- fluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 2-fluoro-5-(2S)-1-(2-(3-aminopropyl)-5-(2-fluoro-5- methoxyphenylmethoxyphenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)-2-methoxypropan-1-one(S)-2-methoxyethyl 2,3- (2S)-1-(2-(3-aminopropyl)-5-(2,3- dichlorophenyldichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 3,4-(2S)-1-(2-(3-aminopropyl)-5-(3,4- dichlorophenyldichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl 3,5-(2S)-1-(2-(3-aminopropyl)-5-(3,5- dichlorophenyldichlorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1-one (S)-2-methoxyethyl thiophen-2-yl(2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-2-yl)-1,3,4-oxadiazol-3(2H)-yl)- 2-methoxypropan-1-one(S)-2-methoxyethyl thiophen-3-yl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-3-yl)-1,3,4-oxadiazol-3(2H)-yl)- 2-methoxypropan-1-one(S)-2-methoxyethyl 5-chlorothiophen- (2S)-1-(2-(3-aminopropyl)-5-(5-2-yl chlorothiophen-2-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1- one (S)-2-methoxyethyl 2-pyridyl(2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(pyridin-2-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one(S)-2-methoxyethyl 3-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one(S)-2-methoxyethyl 4-chloropyridin- (2S)-1-(2-(3-aminopropyl)-5-(4- 3-ylchloropyridin-3-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1- one (S)-2-methoxyethyl3-chloropyridin- (2S)-1-(2-(3-aminopropyl)-5-(3- 2-ylchloropyridin-2-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methoxypropan-1- one acetyl 2,5-1-(2-(3-aminopropyl)-5-(2,5- difluorophenyldifluorophenyl)-2-phenyl-1,3,4-oxadiazol- 3(2H)-yl)ethanone t-butyl2-fluoro-5- 1-(2-(3-aminopropyl)-5-(2-fluoro-5- methoxyphenylmethoxyphenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one t-butyl 3,6-1-(2-(3-aminopropyl)-5-(3,6- difluoropyridin-2-difluoropyridin-2-yl)-2-phenyl-1,3,4- yloxadiazol-3(2H)-yl)-2,2-dimethylpropan-1- one t-butyl 4-fluoropyridin-3-1-(2-(3-aminopropyl)-5-(4-fluoropyridin-3- ylyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2,2- dimethylpropan-1-one

R¹ Name

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(phenyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(pyridin-2-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(pyridin-3-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(3-methylfuran-2-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(2-methylthiazol-5-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(5-methylthiophen-2-yl)methanone

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methylbutan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)butan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-ethylbutan-1-one

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclobutyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(cyclopentyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(tetrahydrofuran-2-yl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(2-fluorocyclohexyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1-methylcyclopropyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1-(trifluoromethyl)cyclopropyl)methanone

(2R)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one

(2R)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxybutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-3,3-dimethylbutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-cyclopropyl-2-hydroxyethanone

(2S)-2-amino-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-cyclopropylethanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1-hydroxycyclopropyl)methanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(1-methoxycyclopropyl)methanone

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxy-2-methylpropan-1-one

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-2-methylpropan-1-one

(2R)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxybutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-3,3-dimethylbutan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-cyclopropyl-2-methoxyethanone

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-cyclopropyl-2-(methylamino)ethanone

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-ethoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-isobutoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-isopropoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-cyclopropoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-tert-butoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(2-methoxyethoxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(benzyloxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-phenoxypropan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(pyridin-2-yloxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(pyridin-3-yloxy)propan-1-one

2-((2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1-oxopropan-2-yloxy)acetic acid

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(trifluoromethoxy)propan-1-one

(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxy-2-phenylethanone

(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(tetrahydrofuran-3-yl)methanone

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methoxypropan-1-one

methyl 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate

ethyl 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxylate

N-((2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-3-methyl-1-oxobutan-2-yl)acetamide

1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propane-1,2-dione

(Z)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(hydroxyimino)propan-1-one

(Z)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(methoxyimino)propan-1-one

R⁴ R⁵ NR²R³ Name H H NH₂ 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H Me NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me Et NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-ethyl-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Et Et NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N,N-diethyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H Et NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-ethyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H 3-pyridyl NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-2-phenyl-N-(pyridin-3-yl)-1,3,4-thiadiazole- 3(2H)-carboxamide H cyclopropyl NH₂2-(3-aminopropyl)-N-cyclopropyl- 5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me 2-pyridyl NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-methyl-2-phenyl-N-(pyridin-2-yl)-1,3,4- thiadiazole-3(2H)-carboxamide H

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-(2-methoxyethyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide Me

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-(2-methoxyethyl)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)- carboxamide Me

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-((S)-2-hydroxy-1-phenylethyl)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)- carboxamide

NH₂ (2-(3-aminopropyl)-5-(2,5- difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)(morpholino)methanone H OH NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H OMe NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H OEt NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-ethoxy-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-(2-methoxyethoxy)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H

NH₂ 2-(3-aminopropyl)-N-tert-butoxy-5- (2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H

NH₂ 2-(3-aminopropyl)-N- (cyclopropylmethoxy)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide Me OH NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me OEt NH₂2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-ethoxy-N-methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-(2-methoxyethoxy)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamideMe

NH₂ 2-(3-aminopropyl)-N-tert-butoxy-5- (2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me

NH₂ 2-(3-aminopropyl)-N- (cyclopropylmethoxy)-5-(2,5-difluorophenyl)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamideiPropyl OH NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-hydroxy-N-isopropyl-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide

NH₂ (2-(3-aminopropyl)-5-(2,5- difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(isoxazolidin- 2-yl)methanone Phenyl

NH₂ 2-(3-aminopropyl)-N-(benzyloxy)- 5-(2,5-difluorophenyl)-N,2-diphenyl-1,3,4-thiadiazole-3(2H)- carboxamide H

NH₂ 2-(3-aminopropyl)-N- cyclopropoxy-5-(2,5-difluorophenyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-(fluoromethoxy)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide Me

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-(fluoromethoxy)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)- carboxamideH

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-2-phenyl-N-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazole- 3(2H)-carboxamide Me

NH₂ 2-(3-aminopropyl)-5-(2,5- difluorophenyl)-N-methyl-2-phenyl-N-(2,2,2-trifluoroethoxy)- 1,3,4-thiadiazole-3(2H)- carboxamideMe OMe NHMe 5-(2,5-difluorophenyl)-N-methoxy- N-methyl-2-(3-(methylamino)propyl)-2-phenyl- 1,3,4-thiadiazole-3(2H)- carboxamide MeOMe NHMe 5-(2,5-difluorophenyl)-2-(3- (dimethylamino)propyl)-N-methoxy-N-methyl-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide Me OMe

2-(3-((S)-2-((S)-2- aminopropanamido)propanamido)propyl)-5-(2,5-difluorophenyl)-N- methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide Me OEt NHMe5-(2,5-difluorophenyl)-N-ethoxy- N-methyl-2-(3-(methylamino)propyl)-2-phenyl- 1,3,4-thiadiazole-3(2H)- carboxamide MeOEt NMe₂ 5-(2,5-difluorophenyl)-2-(3- (dimethylamino)propyl)-N-ethoxy-N-methyl-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide Me OEt

2-(3-((S)-2-((S)-2- aminopropanamido)propanamido)propyl)-5-(2,5-difluorophenyl)-N- ethoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide Me OEt

2-(3-((S)-2-((S)-2- aminopropanamido)propanamido)propyl)-5-(2,5-difluorophenyl)-N- ethoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

R⁴ R⁵ n Y Name H OH 2 OH 5-(2,5-difluorophenyl)-N-hydroxy-2-(2-hydroxyethyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H OH 3 OH5-(2,5-difluorophenyl)-N-hydroxy-2- (3-hydroxypropyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide H OH 2 OP(O)(OH)₂2-(5-(2,5-difluorophenyl)-3- (hydroxycarbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl dihydrogen phosphate H OH 3OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3- (hydroxycarbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me OH 1 OH5-(2,5-difluorophenyl)-N-hydroxy-2- (hydroxymethyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide Me OH 2 OH5-(2,5-difluorophenyl)-N-hydroxy-2- (2-hydroxyethyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide Me OH 3 OH5-(2,5-difluorophenyl)-N-hydroxy-2- (3-hydroxypropyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me OH 1 OP(O)(OH)₂(5-(2,5-difluorophenyl)-3- (hydroxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)methyl dihydrogen phosphate MeOH 2 OP(O)(OH)₂ 2-(5-(2,5-difluorophenyl)-3-(hydroxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl dihydrogen phosphate Me OH 3 OP(O)(OH)₂3-(5-(2,5-difluorophenyl)-3- (hydroxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propyl dihydrogen phosphate HOMe 1 OH 5-(2,5-difluorophenyl)-2- (hydroxymethyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H OMe 2 OH5-(2,5-difluorophenyl)-2-(2- hydroxyethyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide H OMe 3 OH5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H OMe 1 OP(O)(OH)₂(5-(2,5-difluorophenyl)-3- (methoxycarbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)methyl dihydrogen phosphate H OMe 2OP(O)(OH)₂ 2-(5-(2,5-difluorophenyl)-3- (methoxycarbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl dihydrogen phosphate H OMe 3OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3- (methoxycarbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me OMe 1 OH5-(2,5-difluorophenyl)-2- (hydroxymethyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me OMe 2 OH5-(2,5-difluorophenyl)-2-(2- hydroxyethyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me OMe 3 OH5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me OMe 4 OH5-(2,5-difluorophenyl)-2-(4- hydroxybutyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide Me OMe 1 OP(O)(OH)₂(5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)methyl dihydrogen phosphate MeOMe 2 OP(O)(OH)₂ 2-(5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl dihydrogen phosphate Me OMe 3 OP(O)(OH)₂3-(5-(2,5-difluorophenyl)-3- (methoxy(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propyl dihydrogen phosphate MeOMe 4 OP(O)(OH)₂ 4-(5-(2,5-difluorophenyl)-3-(methoxy(methyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butyl dihydrogen phosphate H OEt 3 OH5-(2,5-difluorophenyl)-N-ethoxy-2- (3-hydroxypropyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide H OEt 3 OP(O)(OH)₂3-(5-(2,5-difluorophenyl)-3- (ethoxycarbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate H

3 OH 5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-(2-methoxyethoxy)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-(2-methoxyethoxycarbamoyl)-2-phenyl- 2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate H

3 OH N-tert-butoxy-5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H

3 OP(O)(OH)₂ 3-(3-(tert-butoxycarbamoyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate HO

3 OH N-(cyclopropylmethoxy)-5-(2,5- difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H

3 OP(O)(OH)₂ 3-(3- (cyclopropylmethoxycarbamoyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate Me OEt 3 OH 5-(2,5-difluorophenyl)-N-ethoxy-2-(3-hydroxypropyl)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide Me OEt 3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-(ethoxy(methyl)carbamoyl)-2-phenyl- 2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me

3 OH 5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-(2-methoxyethoxy)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide Me

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-((2-methoxyethoxy)(methyl)carbamoyl)- 2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me

3 OH N-tert-butoxy-5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide Me

3 OP(O)(OH)₂ 3-(3-(tert-butoxy(methyl)carbamoyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me

3 OH N-(cyclopropylmethoxy)-5-(2,5- difluorophenyl)-2-(3-hydroxypropyl)-N-methyl-2-phenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Me

3 OP(O)(OH)₂ 3-(3- ((cyclopropylmethoxy)(methyl)carbamoyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol- 2-yl)propyl dihydrogen phosphatei-propyl OH 3 OH 5-(2,5-difluorophenyl)-N-hydroxy-2-(3-hydroxypropyl)-N-isopropyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide i-propyl OH 3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-(hydroxy(isopropyl)carbamoyl)-2- phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate

3 OH (5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)(isoxazolidin-2- yl)methanone

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-(isoxazolidine-2-carbonyl)-2-phenyl- 2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Phenyl

3 OH N-(benzyloxy)-5-(2,5- difluorophenyl)-2-(3-hydroxypropyl)-N,2-diphenyl-1,3,4-thiadiazole- 3(2H)-carboxamide Phenyl

3 OP(O)(OH)₂ 3-(3-(benzyloxy(phenyl)carbamoyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate H

3 OH N-cyclopropoxy-5-(2,5- difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide H

3 OP(O)(OH)₂ 3-(3-(cyclopropoxycarbamoyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3- dihydro-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate H

3 OH 5-(2,5-difluorophenyl)-N- (fluoromethoxy)-2-(3-hydroxypropyl)-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide H

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-(fluoromethoxycarbamoyl)-2-phenyl- 2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me

3 OH 5-(2,5-difluorophenyl)-N- (fluoromethoxy)-2-(3-hydroxypropyl)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide Me

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3-((fluoromethoxy)(methyl)carbamoyl)- 2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate H

3 OH 5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-2-phenyl-N-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazole- 3(2H)-carboxamide H

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-2-phenyl-3-(2,2,2-trifluoroethoxycarbamoyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate Me

3 OH 5-(2,5-difluorophenyl)-2-(3- hydroxypropyl)-N-methyl-2-phenyl-N-(2,2,2-trifluoroethoxy)-1,3,4- thiadiazole-3(2H)-carboxamide Me

3 OP(O)(OH)₂ 3-(5-(2,5-difluorophenyl)-3- (methyl(2,2,2-trifluoroethoxy)carbamoyl)-2-phenyl- 2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate

Ar² Name 4-fluorophenyl(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(4-fluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one4-methylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-p-tolyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan- 1-one 4-chlorophenyl(2S)-1-(2-(3-aminopropyl)-2-(4-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one4-bromophenyl (2S)-1-(2-(3-aminopropyl)-2-(4-bromophenyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one4-t-butylphenyl (2S)-1-(2-(3-aminopropyl)-2-(4-tert-butylphenyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3,4-dimethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3,4-dimethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-methylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-m-tolyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan- 1-one3,5-dimethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3,5-dimethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one2-chlorophenyl (2S)-1-(2-(3-aminopropyl)-2-(2-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one2-ethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(2-ethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-nitrophenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-nitrophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-hydroxyphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-aminophenyl (2S)-1-(2-(3-aminophenyl)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-carboxyphenyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)benzoic acid3-cyanophenyl 3-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2,3-dihydro-1,3,4-thiadiazol-2- yl)benzonitrile3,4-dichlorophenyl (2S)-1-(2-(3-aminopropyl)-2-(3,4-dichlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-chlorophenyl (2S)-1-(2-(3-aminopropyl)-2-(3-chlorophenyl)-5-(2,5-difluorophenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-ethylphenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(3-ethylphenyl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one3-pyridyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(pyridin-3-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one2-pyridyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(pyridin-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one5-methylthiophen-2-yl(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(5-methylthiophen-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one 1-methyl-1H-imidazol-2-yl(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one 5-methylthiazol-2-yl(2S)-1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-(5-methylthiazol-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

R Ar¹ Name

2-fluorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

2-chlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2-chlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

2-chloro-5- fluorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2-chloro-5-fluorophenyl)-2-phenyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2-fluoro-5- chlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(5-chloro-2-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)-2-methoxypropan-1-one

2,5- dichlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2,5-dichlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

5-chloro-2- methylphenyl (2S)-1-(2-(3-aminopropyl)-5-(5-chloro-2-methylphenyl)-2-phenyl-1,3,4-thiadiazol- 3(2H)-yl)-2-methoxypropan-l-one

2-fluoro-5- trifluoromethyl phenyl(2S)-1-(2-(3-aminopropyl)-5-(2-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2-fluoro-5- methoxyphenyl (2S)-1-(2-(3-aminopropyl)-5-(2-fluoro-5-methoxyphenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,3- dichlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(2,3-dichlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

3,4- dichlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(3,4-dichlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

3,5- dichlorophenyl (2S)-1-(2-(3-aminopropyl)-5-(3,5-dichlorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

thiophen-2-yl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

thiophen-3-yl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(thiophen-3-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

5-chloro thiophen-2-yl (2S)-1-(2-(3-aminopropyl)-5-(5-chlorothiophen-2-yl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(pyridin-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

3-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

3-chloro pyridin-2-yl (2S)-1-(2-(3-aminopropyl)-5-(3-chloropyridin-2-yl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

4-chloro pyridin-3-yl (2S)-1-(2-(3-aminopropyl)-5-(4-chloropyridin-3-yl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(2-(2-aminoethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(2-(aminomethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-(3-(isopropylamino)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-phenyl-2-(3-(pyrrolidin-1-yl)propyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-phenyl-2-(3-(piperidin-1-yl)propyl)-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-(3-(4-methylpiperazin-1-yl)propyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-(2-(methylamino)ethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-(2-(dimethylamino)ethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-(3-hydroxypropyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one

2,5- difluorophenyl (2S)-1-(5-(2,5-difluorophenyl)-2-(2-hydroxyethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)- yl)-2-methoxypropan-1-one

2,5- difluorophenyl N-(3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro- 1,3,4-thiadiazol-2-yl)propyl)methanesulfonamide

2,5- difluorophenyl N-(3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)isobutyramide

2,5- difluorophenyl N-(3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro- 1,3,4-thiadiazol-2-yl)propyl)-3-(dimethylamino)propanamide

X R¹ NR²R³ Name S (S)-2- methoxyethyl

(2S)-1-(2-(3-(cyclopent-2- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one S (S)-2-methoxyethyl

(2S)-1-(2-(3-(cyclopent-3- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one S (S)-2-methoxyethyl

(2S)-1-(2-(3-(cyclohex-2- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one S (S)-2-methoxyethyl

(25)-1-(2-(3-(cyclohex-3- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one S (S)-2-methoxyethyl

(2S)-1-(2-(3-((Z)-cyclohept-4- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one S i-propyl

1-(2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one S i-propyl

1-(2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one S i-propyl

1-(2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one S i-propyl

1-(2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one S NMe₂

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NMe₂

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NMe₂

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NMe₂

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOH

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOH

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOH

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOH

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOH

(Z)-2-(3-(cyclohept-4-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S N(Me)OH

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OH

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OH

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OH

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OH

(Z)-2-(3-(cyclohept-4-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S NHOMe

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOMe

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOMe

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOMe

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S NHOMe

(Z)-2-(3-(cyclohept-4-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide S N(Me)OMe

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OMe

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OMe

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OMe

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide S N(Me)OMe

(Z)-2-(3-(cyclohept-4-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)- carboxamide O (S)-2- methoxyethyl

(2S)-1-(2-(3-(cyclopent-2- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one O (S)-2-methoxyethyl

(2S)-1-(2-(3-(cyclopent-3- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one O (S)-2-methoxyethyl

(2S)-1-(2-(3-(cyclohex-2- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one O (S)-2-methoxyethyl

(2S)-1-(2-(3-(cyclohex-3- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one O (S)-2-methoxyethyl

(2S)-1-(2-(3-((Z)-cyclohept-4- enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2- methoxypropan-1-one O i-propyl

1-(2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one O i-propyl

1-(2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one O i-propyl

1-(2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one O i-propyl

1-(2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one O NMe₂

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NMe₂

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NMe₂

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NMe₂

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N,N-dimethyl-2- phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOH

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOH

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOH

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOH

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O N(Me)OH

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OH

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OH

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OH

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O NHOMe

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOMe

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOMe

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOMe

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O NHOMe

(Z)-2-(3-(cyclohept-4-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-2-phenyl-1,3,4-oxadiazole-3(2H)-carboxamide O N(Me)OMe

2-(3-(cyclopent-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OMe

2-(3-(cyclopent-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OMe

2-(3-(cyclohex-2-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OMe

2-(3-(cyclohex-3-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide O N(Me)OMe

(Z)-2-(3-(cyclohept-4-enylamino)propyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-oxadiazole-3(2H)- carboxamide

Example 123

The activity of the compounds of the present invention may be determinedby the following procedure. The assays were conducted at 30° C. in aCostar 3695 (96-well, polystyrene, ½-area, clear) plate in a finalvolume of 50 μL. Hydrolysis of ATP was monitored in a system thatcoupled the product ADP to the oxidation of NADH using pyruvate kinaseand lactate dehydrogenase. Assay mixtures contained the following: 20 mMK⁺Pipes, pH 7.0, 0.01% Triton X-100, 2% DMSO, 25 mM KCl, 2 mM MgCl₂, 1mM DTT, 25 μM ATP, 1 mM phospho(enol)pyruvate, 200 μM NADH, 7.9 U/mLpyruvate kinase, 9 U/mL lactate dehydrogenase, 0.25 μM bovinemicrotubules, 20 μM paclitaxel and 20 nM Eg5. The concentration ofinhibitor was typically varied over the range of 10-200,000 nM. Thereaction was monitored kinetically in an absorbance-based plate readerfor a period of 10 minutes. Velocities were estimated from linear fitsto the progress curves and were expressed as POC (percent of uninhibitedcontrol wells). IC₅₀'s were estimated from the POC data using a standard4-parameter logistical model and compared to a control inhibitor run ineach plate. In this assay, compounds of the invention exhibited an IC₅₀of less than 50 μM.

Example 124

The ability of the compounds of the present invention to inhibitcellular viability may be determined by the following procedure. Cellsfrom a variety of established tumor cell lines, e.g., HeLa, were platedin Costar 3904 96-well plates, in growth medium for the cell line (forHeLa:DMEM high glucose, L-glutamine, 20 mM Hepes, 10% FBS), at a densitythat allowed for logarithmic growth over the 72 hour period of the assay(HeLa: 1000 cells/well), and incubated at 37° C., 5% CO₂ overnight. Thefollowing day, one-tenth volume of a 10× concentration of compounds wasadded to the wells in an 11-point dilution series. The dilution serieswas composed of an initial 1:2 dilution in DMSO, followed by a 1:20dilution in growth medium, for a final DMSO concentration on cells of0.5%. Control wells were treated with 0.5% DMSO. The typical range ofdilution was 2.5 μM to 1 nM, which was expanded to 50 μM to 50 μMdepending on the potency of the compound. Once compound was added to thecells, plates were incubated as above. After 72 hour incubation, 20 μLresazurin solution (Cell Titer Blue, Promega G8081) was added to allwells and the plates incubated for an additional 2 hours. Viable cellsconvert resazurin to resorufin, a fluorescent end product. The plate wasread on a fluorescent plate reader at 560 nm excitation/590 nm emission.The fluorescent signal of the control wells was defined as 100% and thepercent of control signal for each well of a dilution series for thecompound was defined as: (fluorescent signal of treated well)×(averagefluorescent signal of the control well)⁻¹×100. The EC₅₀ for inhibitionof viability was determined from the inflection point of a standard4-parameter logistical curve fitted to the values obtained. In thisassay, the compounds of the invention exhibited an EC₅₀ of less than 50μM.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A compound of the Formula

and resolved enantiomers, diastereomers, racemic mixtures andpharmaceutically acceptable salts thereof, wherein: X is S, R isZ—NR²R³, Z—OH, or Z—OP(═O)(OR^(a))(OR^(a)); R¹ is alkyl, alkenyl,alkynyl, aryl, heteroaryl, saturated or partially unsaturatedcycloalkyl, saturated or partially unsaturated heterocycloalkyl, —OR³,—NR⁴OR⁵, CR^(b)(═NOR^(c)), C(═O)R^(a), or —NR⁴R⁵, wherein said alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d),—NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a),—OP(═O)(OR^(a))₂, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; Ar¹ ispyridyl and Ar² is phenyl, wherein said phenyl and pyridyl areoptionally substituted with one or more groups independently selectedfrom F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, saturated orpartially unsaturated cycloalkyl, saturated or partially unsaturatedheterocycloalkyl, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, OR^(a), —O(C═O)OR^(d),—OP(═O)(OR^(a))(OR^(a)), NR^(a)R^(b), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b),SR⁶, SOR⁶, SO₂R⁶, —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b) and —NR^(c)C(═O)NR^(a)R^(b); R² is hydrogen, —C(═O)R⁴,—SO₂R⁶, alkyl, alkenyl, alkynyl, saturated or partially unsaturatedcycloalkyl, a natural or unnatural amino acid, or a polypeptide of twoor more amino acids independently selected from natural and unnaturalamino acids, wherein said alkyl, alkenyl, alkynyl, and cycloalkyl areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —OR^(a),alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl; R³ is hydrogen, —C(═O)R⁴, alkyl, alkenyl, alkynyl, orsaturated or partially unsaturated cycloalkyl, wherein said alkyl,alkenyl, alkynyl, and cycloalkyl are optionally substituted with one ormore groups independently selected from oxo (with the proviso that it isnot substituted on said aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—OP(═O)(OR^(a))₂, —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —OR^(a),alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl, or R² and R³ together with the nitrogen atom to whichthey are attached form a saturated or partially unsaturated heterocyclicring which may include 1 to 3 additional heteroatoms, in addition to thenitrogen atom to which said R² and R³ are attached, selected from N, Oand S, wherein said heterocyclic ring is optionally substituted with oneor more groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocycloalkyl and heterocyclylalkyl; R⁴ and R⁵ are independently H,trifluoromethyl, difluoromethyl, fluoromethyl, alkyl, alkenyl, alkynyl,saturated or partially unsaturated cycloalkyl, saturated or partiallyunsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom oxo (with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(d), —NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl andheterocyclylalkyl, or R⁴ and R⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated heterocyclic ringwhich may include 1 to 3 additional heteroatoms, in addition to theheteroatoms to which said R⁴ and R⁵ are attached, selected from N, O andS, wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b),—OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; R⁶is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,saturated or partially unsaturated cycloalkyl, saturated or partiallyunsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more groups independently selected from oxo (with the provisothat it is not substituted on said aryl or heteroaryl), halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b),—OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl;R^(a) is hydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturatedor partially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl or saturated or partiallyunsaturated heterocyclylalkyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl are optionallysubstituted with one or more groups independently selected from oxo(with the proviso that it is not substituted on said aryl orheteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,—O(C═O)OR^(h), —NR^(f)SO₂R^(h), —SO₂NR^(e)R^(f), —C(═O)R^(e),—C(═O)OR^(e), —OC(═O)R^(e), —NR^(f)C(═O)OR^(h), —NR^(f)C(═O)R^(e),—C(═O)NR^(e)R^(f), —NR^(e)R^(f), —NR^(c)C(═O)NR^(e)R^(f),—NR^(c)C(NCN)NR^(e)R^(f), —OR^(e), alkyl, alkenyl, alkynyl, saturated orpartially unsaturated cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, saturated or partially unsaturated heterocycloalkyl andheterocyclylalkyl; R^(b), R^(c), R^(f) and R^(g) are independentlyhydrogen or alkyl, or R^(a) and R^(b) together with the atom to whichthey are attached form a 4 to 10 membered saturated or partiallyunsaturated heterocyclic ring which may include 1 to 3 additionalheteroatoms, in addition to the nitrogen atom to which said R^(a) andR^(b) are attached, selected from N, O and S; R^(d) and R^(h) areindependently trifluoromethyl, alkyl, saturated or partially unsaturatedcycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, saturated orpartially unsaturated heterocycloalkyl or heterocyclylalkyl; R^(e) ishydrogen, trifluoromethyl, alkyl, alkenyl, alkynyl, saturated orpartially unsaturated cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, saturated or partially unsaturatedheterocycloalkyl or heterocyclylalkyl; and Z is alkylene having from 1to 6 carbons, or alkenylene or alkynylene each having from 2 to 6carbons, wherein said alkylene, alkenylene and alkynylene are optionallysubstituted with one or more groups independently selected from oxo,halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —O(C═O)OR^(d),—NR^(b)SO₂R^(d), —SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a),—OC(═O)R^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b),—NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocycloalkyl and heterocyclylalkyl.
 2. The compound of claim 1,wherein Ar¹ is optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b), NO₂, CN,C(═O)OR^(a), alkyl, and CF₃.
 3. The compound of claim 2, wherein Ar¹ andAr² are independently and optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b), NO₂, CN,C(═O)OR^(a), alkyl, and CF₃.
 4. The compound of claim 1, wherein R isZ—NR²R³ or Z—OH.
 5. The compound of claim 4, wherein Z is substituted orunsubstituted alkylene.
 6. The compound of claim 5, wherein Z issubstituted or unsubstituted propylene.
 7. The compound of claim 4,wherein R² and R³ are independently selected from H, alkyl, saturated orpartially unsaturated cycloalkyl, an amino acid, and a dipeptide,wherein said alkyl and cycloalkyl are optionally substituted.
 8. Thecompound of claim 1, wherein R¹ is —NR⁴OR⁵.
 9. The compound of claim 8,wherein R⁴ and R⁵ are independently selected from H, alkyl, saturated orpartially unsaturated cycloalkyl, and heteroaryl.
 10. The compound ofclaim 1, wherein R¹ is alkyl, cycloalkyl, heterocycloalkyl, O-alkyl,OR^(a), aryl, heteroaryl, CR^(b)(═NOR^(c)), or C(═O)R^(a), wherein saidalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from OR^(a),NR^(a)R^(b), halogen, cycloalkyl, alkyl, aryl and CF₃.
 11. The compoundof claim 1, which is

wherein: R^(x) and R^(y) are independently H, alkyl, saturated orpartially unsaturated cycloalkyl or aryl, wherein said alkyl, cycloalkyland aryl are optionally substituted with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on said aryl), halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—OCH₂C(═O)OR^(a), —NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a),—C(═O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(c)C(═O)NR^(a)R^(b),—NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, or R^(x) and R^(y) together with the atom to whichthey are attached form a saturated or partially unsaturated carbocyclicring or heterocyclic ring having one or more heteroatoms independentlyselected from N, O and S, wherein said carbocyclic and heterocyclicrings are optionally substituted with one or more groups independentlyselected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(d), —NR^(b)SO₂R^(d),—SO₂NR^(a)R^(b), —C(═O)R^(a), —C(═O)OR^(a), —OC(═O)R^(a),—NR^(b)C(═O)OR^(d), —NR^(b)C(═O)R^(a), —C(═O)NR^(a)R^(b), —NR^(a)R^(b),—NR^(c)C(═O)NR^(a)R^(b), —NR^(c)C(NCN)NR^(a)R^(b), —OR^(a), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl; or R^(a) andR^(x) together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring which may include 1to 3 additional heteroatoms, in addition to the oxygen atom to whichsaid R^(a) is attached, selected from N, O and S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —O(C═O)OR^(h), —NR^(f)SO₂R^(h),—SO₂NR^(e)R^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—NR^(f)C(═O)OR^(h), —NR^(f)C(═O)R^(e), —C(═O)NR^(e)R^(f), —NR^(e)R^(f),—NR^(g)C(═O)NR^(e)R^(f), —NR^(c)C(NCN)NR^(e)R^(f), —OR^(e), alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl and heterocyclylalkyl.
 12. Thecompound of claim 11, wherein at least one of R^(x) and R^(y) is not H.13. The compound of claim 12, wherein R^(a) is H or alkyl.
 14. Thecompound of claim 13, wherein R^(x) is alkyl.
 15. The compound of claim11, wherein R is Z—NR²R³ or Z—OH.
 16. The compound of claim 15, whereinR² and R³ are independently selected from H, alkyl, saturated orpartially unsaturated cycloalkyl, an amino acid, and a dipeptide,wherein said alkyl and cycloalkyl are optionally substituted.
 17. Thecompound of claim 11, wherein R¹ is —NR⁴OR⁵.
 18. The compound of claim17, wherein R⁴ and R⁵ are independently selected from H, alkyl,saturated or partially unsaturated cycloalkyl, and heteroaryl.
 19. Thecompound of claim 18, wherein R⁴ and R⁵ are alkyl.
 20. The compound ofclaim 11, wherein R¹ is alkyl, cycloalkyl, heterocycloalkyl, O-alkyl,OR^(a), aryl, heteroaryl, CR^(b)(═NOR^(c)), or C(═O)R^(a), wherein saidalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from OR^(a),NR^(a)R^(b), halogen, cycloalkyl, alkyl, aryl and CF₃.
 21. The compoundof claim 11, wherein Ar¹ is optionally substituted with one or moregroups independently selected from F, Cl, Br, I, OR^(a), NR^(a)R^(b),NO₂, CN, C(═O)OR^(a), alkyl, and CF₃.
 22. The compound of claim 11,wherein Ar¹ and Ar² are independently and optionally substituted withone or more groups independently selected from F, Cl, Br, I, OR^(a),NR^(a)R^(b), NO₂, CN, C(═O)OR^(a), alkyl, and CF₃.
 23. A compound ofclaim 1, selected from:

R Ar¹ Name

2-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(pyridin-2-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

3-pyridyl (2S)-1-(2-(3-aminopropyl)-2-phenyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

3-chloro pyridin-2-yl (2S)-1-(2-(3-aminopropyl)-5-(3-chloropyridin-2-yl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

4-chloro pyridin-3-yl (2S)-1-(2-(3-aminopropyl)-5-(4-chloropyridin-3-yl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2- methoxypropan-1-one

and resolved enantiomers and diastereomers thereof.
 24. A method oftreating arthritis, graft rejection, or inflammatory bowel disease in ahuman or animal comprising administering to said human or animal aneffective amount of a compound of claim 1 or a pharmaceuticalcomposition comprising said compound.